Development and optimisation of nanoparticle delivery systems for antimicrobials and growth factors to reduce orthopaedic infections and to aid fracture repair

Abstract

Chitosan, alginate, liposome and PLGA nanoparticle delivery systems were investigated to develop systems to enhance bone healing and treat osteomyelitis. Specifically they were intended to increase the rate of bone growth to enhance the healing of a break or fracture using the osteogenic growth factor BMP-2 and to deliver antimicrobials that would be capable of preventing/treating osteomyelitis. Each formulation was optimised to produce ideal characteristics in terms of size (100 to 400 nm), PDI (< 0.5), zeta potential (generally negative) and in vitro release studies for metronidazole, gentamicin and model growth factor (BSA) loaded nanoparticles. The optimised delivery system (chitosan nanoparticles) was loaded with BMP-2 and further investigated.

Entrapment varied between metronidazole (10 to 35 %), gentamicin (10 to 65 %) and BSA (17 to 91 %). In vitro drug release also varied between the formulations andagents, with several formulations showing total release over the course of seven days with others releasing around 15 %.

Antimicrobial activity varied between formulations with chitosan nanoparticles demonstrating the greatest efficacy against C. difficile (producing zones between 37 to 44 mm and showing complete reduction in colony forming units between 3 to 6 hours after exposure) and against both P. aeruginosa and MRSA (with zones ranging from 13 to 24 mm and complete reduction in colony forming units observed between 3 to 24 hours).

Studies of the BSA loaded chitosan nanoparticles were found to be optimal for loading with BMP-2 showing ideal characteristics. In the SAOS-2 cell line the BMP-2 loaded nanoparticles demonstrated enhanced production of PNP which indicated increased ALP activity over 14 days. This indicates that the SAOS-2 cells were metabolically active and differentiating for longer in the presence of the BMP-2 loaded nanoparticles. These optimised chitosan nanoparticle formulations loaded with antimicrobials or BMP-2 show promise for use in orthopaedic complications. Their true potential would however need to be futher examined in vivo using an animal model to demonstrated efficacy against the disease state in a living entitity.

Date of Award	Aug 2021
Original language	English
Sponsors	Department for Employment and Learning (DEL)
Supervisor	Anthony McHale (Supervisor), Susan Hawthorne (Supervisor) & Deborah Lowry (Supervisor)