pH-responsive, redox-sensitive hollow particles for the repair of load-bearing soft tissue

  • Robert Bird

Student thesis: Phd


This thesis presents an investigation of pH-responsive, redox-sensitive poly(MMA-co- MAA) and poly(EA-co-MAA) hollow particles for the repair of load-bearing soft tissues, such as articular cartilage and the intervertebral disc. Hollow particles continue to attract major interest due to their numerous potential applications. The new method for hollow particle preparation presented in this thesis does not require the use of a colloidal template and is well suited for scaling up. Hollow particles were formed using linear poly(MMA-co-MAA) and poly(EA-co-MAA) aliphatic copolymers synthesised using free-radical chain copolymerisation performed in solution. These copolymers were dissolved in dichloromethane using methanol as a cosolvent and emulsified in water. Diffusion of the methanol into the aqueous phase prompts precipitation of the copolymer at the droplet/water interface. The more hydrophobic copolymers containing less MAA showed improved morphology compared to copolymers containing more MAA. Also, poly(EA-co-MAA) hollow particles had a more spherical morphology than poly(MMA-co-MAA) hollow particles with equivalent MAA contents. This was attributed to the lower Tg of the EA structural monomer, which resulted in more flexible particle shells. Unusually, during potentiometric titration of uncrosslinked hollow particles, the pH of the system decreased with increasing neutralisation. This behaviour is thought to be due to the unfolding of copolymer chains, exposing shielded carboxyl groups. The random structure of the copolymers is believed to be necessary for this behaviour. Crosslinked particles became swollen when the pH was increased using buffers. Concentrated dispersions formed self supporting gels, due to steric confinement, at 5 wt.%. The crosslinking process was performed by functionalising with cystamine using carbodiimide chemistry. This introduced disulphide crosslinks; which could be cleaved under reducing conditions at high pH, dissolving the gels. This ability to reduce the hollow particle shells to their constituent linear copolymer chains gives potential for natural removal from the body via extraction by the renal system. pH-triggered loading and release of a hydrophilic dye using crosslinked hollow particles was demonstrated. The similarity of the particle formation process to traditional solvent evaporation also allowed the loading of a hydrophobic dye. However, these particles were not crosslinked so release following swelling could not be investigated. Cystamine-crosslinked systems suffered from degradation due to thiol-disulphide exchange at high pH (~ pH 8). Crosslinking of one system was performed using 2-amino ethyl methacrylate (AEM). This introduced covalent, vinyl intra-shell crosslinking; which did not break down at high pH. Additional AEM was also used to allow inter-particle UVcrosslinking to form doubly crosslinked (DX) hollow-particle hydrogels. These gels did not re-disperse in buffer. To our knowledge, this is the first example of a covalent hydrogel formed from pH-responsive hollow particles. The DX gels offer improved mechanical properties compared to the singly crosslinked, physical gels. Freeze-dried samples of all of the gels produced during this study showed highly porous structures when observed using SEM. The rapid diffusion of FITC-dextran through a sample of DX gel indicates that these pores were interconnected. This is beneficial as it encourages tissue ingrowth, in addition to allowing the rapid diffusion of nutrients, oxygen and cell waste in vivo.
Date of Award31 Dec 2012
Original languageEnglish
Awarding Institution
  • The University of Manchester
SupervisorBrian Saunders (Supervisor) & Anthony Freemont (Supervisor)


  • redox
  • soft tissue
  • pH responsive
  • Colloid
  • hollow
  • gel
  • particle

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