Development of multifunctional polydimethylsiloxane-based polyurethanes as an ‘off-the-shelf’ alloplastic platform for urological reconstruction

Abstract

Over 400 million patients suffer from urinary bladder-associated physiological disorders globally, which often necessitate surgical intervention for a reconstructive procedure. The current gold standard for bladder reconstruction, an autologous graft, is proven not to be an ideal substitute in clinics. Such unmet clinical needs drive the continuous surge for structural and functional substitutes of urinary tissues, including ureters, bladder-wall, and urethra. Against this backdrop, the present dissertation explores a biomaterial-based, functionalised alloplastic platform for urological reconstruction. This strategy for an alloplastic urinary tissue encompasses a biostable, 'off-the-shelf' available therapeutic option that simplifies and shortens surgical treatment. Furthermore, it presents the potential to evade the challenges and complications of autografts and scaffold-based regenerative techniques. Considering the prerequisites of a urological alloplast, the combination of polydimethylsiloxane and thermoplastic polyurethanes (TPU/PDMS) is deemed most advantageous. The synergistic integration of varying contents of PDMS within the molten TPU matrix is realised through a processing methodology of dynamic vulcanisation (DV). The experimental outcomes are evaluated and correlated with different phenomenological models to understand DV induced strengthening of structure. The theoretical predictions, in conjunction with material property characterisation, allow a better understanding of the improved interfacial behaviour and superior performance of the crosslinked polymer system. The in situ compatibilised blends are further investigated for clinically relevant viscoelastic properties to sustain high pressure, large distensions, and surgical handling/manipulation. Moreover, non-exhaustive chemical strategies are harnessed to counter urinary tract infections through the covalent incorporation of polycationic moieties. The new generation alloplasts, endowed with contact killing surfaces, are assessed for their efficacy in pathogenically infected artificial urine. In addition, the adhesion and proliferation of murine fibroblasts on different polymeric compositions to establish their cytocompatibility. Building further upon the knowledge of the antibacterial and antifouling activity of polycationic modifications, layer-by-layer (LbL) assembled multifunctional surface grafting are conceived to sustain long-term stability in a urinary environment, to suppress encrustation and biofilm formation. The performance of the single-step and LbL-grafted blends is benchmarked against the conventional urological alloplasts, using a customised lab-scale bioreactor set-up. Post-six weeks of incubation in the dynamic assembly simulating ureasepositive microbial infection, the contact-active blends exhibited a remarkable ability to resist calcium and magnesium encrustation, while retaining adequate grafting integrity. As high as 4-fold log reduction in the planktonic growth of bacterial strains associated with bladder stones and renal calculi is recorded. In vitro cellular assessment is carried out with human keratinocytes and human embryonic kidney cells to evaluate the cytocompatibility of the surface grafted blends against the medical-grade control polymer. Finally, the optimum LbL grafted formulations are investigated for their performance in a phase-I pre-clinical study utilising human urine samples collected from 129 patients. The newly developed blends meet the clinically desirable attributes and present a strong potential as a stable, contact-active, antiencrustation biomaterial platform for urinary implantation. Summarising, this dissertation contemplates the new-generation, infection and encrustationresistant alloplasts. In pursuit of this vision, multifunctional polymeric biomaterials are designed to sustain desirable performance in a urinary environment. These next-gen biomaterials pave the way for an alloplastic platform that can integrate into clinical practice to improve the quality of modern urological treatment.