Laser powder bed fusion-centred approach to enable local drug delivery from a cementless hip stem

ENGLISH ABSTRACT: Periprosthetic joint infection (PJI) resulting from colonisation of implant surfaces by pathogenic bacteria and subsequent biofilm formation is a devastating complication following total hip arthroplasty. It significantly reduces a patient’s quality of life and, in severe cases, can result in amputation or mortality. Treatment of PJI is associated with a substantial burden on healthcare and economic resources. The importance of research towards innovations in PJI prevention and treatment is emphasised. Local delivery of antimicrobial drugs is an effective approach to prevent and treat PJI as it enables high local drug concentrations while avoiding systemic side effects. Current practice is considered sub-optimal and appreciable research exists on the improvement of local drug delivery strategies. For cementless hip stems the focus tends to be on coatings and conditioning of the external implant surface. A significant research gap exists between external and internal drug delivery strategies where ‘internal’ refers to the incorporation of reservoir structures within the implant. Therefore, a prototype strategy utilising the internal volume of a cementless stem for a reservoir from which an antimicrobial drug can be delivered directly to the implant surface was investigated. The challenge of fabricating a cementless hip stem with intricate internal geometries can be effectively addressed through metal additive manufacturing (MAM). Industry is steadily incorporating MAM into process chains as the main production technology for the fabrication of high-value functional components. Laser powder bed fusion (LPBF) was applied in this study as MAM technology to fabricate a Ti6Al4V ELI demonstrator cementless hip stem with local drug delivery functionality. This required an interdisciplinary approach, for which a problem solving framework has been synthesised to aid in process chain development from an LPBF-centred perspective. The overall problem was decomposed into integrated partial and single problems which were systematically investigated through literature study and experimentation. An LPBF-centred solution was developed for the direct integration of permeable structures in a dense part using an in-process assembly method. Different levels of porosity were induced into permeable thin walls according to a systematically identified window for ranges of the process parameters, laser power and scanning speed. This resulted in tailorable release profiles for the model antibiotic vancomycin from an aqueous formulation. Released vancomycin retained its antibiotic efficacy against Staphylococcus aureus Xen 36 (methicillin sensitive) and Staphylococcus aureus Xen 31 (methicillin resistant), representing two of the most frequent pathogens in PJI. Solutions for single problems were recomposed for integrated solutions to partial problems, and subsequently for an overall prototype solution. The overall solution cementless hip stem prototype effectively prevented surface colonisation by Staphylococcus aureus Xen 31, confirming the efficacy of the developed local drug delivery strategy. These results were used to inductively refine the LPBF-centred interdisciplinary problem solving framework. The original contribution of the research corresponds to the experimentation and framework development phases respectively. This involves the systematic investigation of LPBF to enable local drug delivery and an LPBF-centred approach for interdisciplinary problem solving. Lastly, it contributes to the advancement of LPBF by demonstrating the application efficacy of the prototype solution.AFRIKAANSE OPSOMMIMG: Periprostetiese gewrigsinfeksie (PJI) as ‘n gevolg van implantaatoppervlak kolonisasie deur patogeniese bakterieë en biofilm formasie is ’n ernstige komplikasie na totale heupartroplastiek. Dit verlaag ’n pasiënt se lewenskwaliteit merkwaardig en kan in ernstige gevalle lei tot amputasie of sterfte. Behandeling van PJI word geassosieer met ’n substansiële las op gesondheids- en ekonomiese middele. Die belangrikheid van navorsing vir innovasies in PJI voorkoming en behandeling word benadruk. Lokale toediening van antimikrobiese medikamente is ‘n effektiewe benadering om PJI te voorkom en te behandel deurdat hoë lokale antimikrobiese konsentrasies gehandhaaf kan word sonder sistemiese newe- effekte. Huidige praktyk word beskou as suboptimaal en veel navorsing bestaan vir die verbetering van lokale toedieningsstrategieë. Vir ongesementeerde heupstamme is die fokus op bedekkings en kondisionering van die eksterne implantaatoppervlak. ’n Beduidende gaping bestaan tussen eksterne en interne lokale toedieningsstrategieë waar ‘intern’ verwys na die inkorporasie van reservoirstrukture binne die implantaat. Daarom was ’n prototipestrategie vir die benutting van die interne volume van ’n ongesementeerde heupstam vir ’n reservoir waar vanuit medikamente direk na die implantaatoppervlak toegedien kan word ondersoek. Die uitdaging om ’n ongesementeerde heupstam met ingewikkelde interne geometrieë te vervaardig kan effektief aangespreek word deur metaal toevoegingsvervaardiging (MAM). ndustrie is stelselmatig besig om MAM in proseskettings te inkorporeer as die hoof produksietegnologie vir die vervaardiging van hoë-waarde funksionele komponente. Laser poeierbed fusie (LPBF) is toegepas in hierdie studie as MAM-tegnologie om ’n Ti6Al4V ELI demonstrasie ongesementeerde heupstam met lokale medikament toedieningsfunksie te vervaardig. Dit het ’n interdissiplinêre benadering vereis waarvoor ’n probleemoplossingsraamwerk gesintetiseer was om die proseskettingontwikkeling vanuit ’n LPBF-gesentreerde perspektief te ondersteun. Die algehele probleem was opgebreek in geïntegreerde deel- en enkelprobleme wat sistematies ondersoek was deur literatuur studie en eksperimentasie. ’n LPBF-gesentreerde oplossing was ontwikkel vir die direkte integrasie van poreuse strukture in ’n digte part met ’n in-proses monteermetode. Verskeie vlakke van porositeit was geïnduseer in deurlaatbare dun wande volgens ’n stelselmatige geïdentifiseerde venster vir waardes vir die prosesparameters laser sterkte en skandeer spoed. Dit het geresulteer in aanpasbare vrystellingsprofiele vir die modelantibiotika vankomisien vanuit ’n wateroplossing. Vrygestelde vankomisien het antibiotiese effektiwiteit behou teen Staphylococcus aureus Xen 36 (metisillien sensitief) en Staphylococcus aureus Xen 31 (metisillien weerstandig), verteenwoordigend van twee van die mees frekwente patogene in PJI. Oplossings vir enkelprobleme was geherkombineer tot geïntegreerde oplossings vir deelprobleme, en gevolglik vir ’n algehele prototipe-oplossing. Die algehele oplossing ongesementeerde heupstam prototipe het oppervlakkolonisasie deur Staphylococcus aureus Xen 31 effektief verhoed wat die funksionaliteit van die ontwikkelde lokale medikament toedieningsstrategie bevestig. Die resultate was induktief gebruik om die LPBF-gesentreerde interdissplinêre probleemoplossingsraamwerk te verfyn. Die oorspronklike bydrae van die navorsing korrespondeer respektiewelik tot die eksperimentele- en raamwerkontwikkelingsfases. Dit betrek die sistematiese ondersoek van LPBF om lokale medikamenttoediening te bewerkstellig en ’n LPBF-gesentreerde raamwerk vir interdissiplinêre probleemoplossing. Laastens dra dit by tot die bevordering van LPBF deur die toepassingseffektiwiteit van die prototipe-oplossing te demonstreer.Doctora