Self-Healing Dynamic Hydrogel as Injectable Shock-Absorbing Artificial Nucleus Pulposus

Abstract

The intervertebral discs (IVDs) provide unique flexibility to the spine and exceptional shock absorbing properties under impact. The inner core of the IVD, the nucleus pulposus (NP) is responsible for this adaptive behavior. Herein, we evaluate an injectable, self-healing dynamic hydrogel (DH) based on gold(I)-thiolate/disulfide (Au-S/SS) exchange as NP replacement in a spine motion segment model. For the first time, we report the application of dynamic covalent hydrogels inside biological tissues. The dynamic exchange between Au-S species and disulfide bonds (SS) resulted in self-healing ability and frequency-dependent stiffness of the hydrogel, which was also confirmed in spine motion segments. Injection of preformed DH into nucleotomized IVDs restored the full biomechanical properties of intact IVDs, including the stiffening effect observed at increasing frequencies, which cannot be achieved with conventional covalent hydrogel. DH has the potential to counteract IVD degeneration associated with high frequency vibrations. Self-healing properties, confirmed by rheology studies and macroscopic observation after injection, were required to inject preformed DH, which recovered its mechanical integrity and microstructure to act as an artificial NP. On the other hand, covalent hydrogel did not show any restoration of NP properties as this conventional material suffered irreversible damages after injection, which demonstrates that the dynamic properties are crucial for this application. The persistence of DH in the IVD space following cyclic high-frequency loading, confirmed by tomography after mechanical testing, suggests that this material would have long life span as an injectable NP replacement material.

Toward Stimuli‐Responsive Dynamic Thermosets through Continuous Development and Improvements in Covalent Adaptable Networks (CANs)

“…Soft CANs are excellent candidates as long‐term tissue replacements, as demonstrated by gold–thiolate and disulfide crosslinks in an artificial nucleus pulposus hydrogel that recapitulated of the biomechanical characteristics of healthy intervertebral discs 97. Additionally, similar CANs were used in a network containing agglomerates of bioactive glass nanoparticles as a scaffold for in situ bone regeneration 98.…”

A Recent Perspective on Noncovalently Formed Polymeric Hydrogels

“…The interchange and lifetime, as well as strength can be changed with different environmental stimuli to create stimuli‐responsive materials. Noncovalent hydrogels can be pH and ionic strength responsive due to underlying electrostatic interactions, redox responsive based off thiol‐disulfide exchange, temperature responsive due to the hydrophobic effect, glucose responsive due to reversible boronate interactions between glucose and phenylboronic acid and respond to mechanical cues due to multiple weak noncovalent interactions that break upon high shear stress ,,,. Furthermore, as responsiveness is mostly linked to some noncovalent interaction, these noncovalently formed hydrogels offer the potential of being maximally responsive materials.…”

“…It shows frequency dependent mechanical stiffness similar to other noncovalent hydrogels. Cyclic tension/compression tests show that it has similar biomechanical shock absorbing properties as the nucleus pulposus in intervertebral discs, indicating that it has some potential application for replacement of shock absorbing tissues . Thiol‐disulfide exchange has previously been used to allow hydrogel formation to be initiated and stopped by changing of the pH in the system in a “living” controlled hydrogel formation .…”

Synthesis and Biomedical Applications of Self-healing Hydrogels

“…These hydrogels showed reversible mechanical properties and frequency-dependent stiffness/shock-absorbing properties at the physiological pH due to the metal(I)-thiolate/disulfide exchange. The potential of the hydrogel as an artificial nucleus pulposus for the intervertebral discs was demonstrated via a bovine ex vivo model using axial compression-tension cycles at different frequencies followed by creep experiments and μCT analysis (Pérez-San Vicente et al, 2017 ). Moreover, the hydrogels incorporating bioactive glass nanoparticles led to the stiffer properties for bone regeneration (Gantar et al, 2016 ).…”