MMP9-sensitive polymers mediate environmentally-responsive bivalirudin release and thrombin inhibition.

Area of Science:

• Biomaterials Science
• Neuroscience
• Drug Delivery

Background:

• Spinal cord contusion injuries cause significant inflammation and scarring.
• Current treatments have limitations in addressing localized inflammatory responses.
• Matrix metalloproteinase-9 (MMP9) is upregulated at injury sites, presenting a therapeutic target.

Purpose of the Study:

• To synthesize and evaluate MMP9-responsive bivalirudin-HPMA copolymers for local administration.
• To assess the release kinetics of bivalirudin from hyaluronic acid/methylcellulose (HAMC) hydrogels.
• To investigate the in vivo efficacy of the bivalirudin copolymer system in a rat spinal cord contusion model.

Main Methods:

• Synthesis of bivalirudin-conjugated HPMA copolymers responsive to MMP9.
• Encapsulation of copolymers within HAMC hydrogels for sustained release.
• Administration of copolymers to rat spinal cord contusion injury models.
• Assessment of cellular proliferation and astrogliosis at the injury site.

Main Results:

• Polymer-conjugated bivalirudin maintained therapeutic activity and showed MMP9-mediated release.
• HAMC hydrogels provided prolonged release of bivalirudin copolymers compared to free bivalirudin.
• In vivo administration reduced cellular proliferation and astrogliosis in rat spinal cord injury models.

Conclusions:

• MMP9-responsive bivalirudin-HPMA copolymers demonstrate effective, localized drug delivery.
• The HAMC hydrogel system facilitates sustained release and therapeutic intervention.
• This copolymer-hydrogel system shows promise for mitigating acute inflammation and chronic scarring in spinal cord injuries.