Ultrasound Triggered Gelation to Treat Discogenic Lower Back Pain

Motivation: Lower back pain (LBP) is one of the leading causes of global disability. LBP and related radicular leg pain are closely linked to intervertebral disc (IVD) degeneration, which accounts for approximately 40% of the estimated 619 million LBP cases worldwide. Currently, there are two diametrically opposed treatment options for this condition: conservative physiotherapy to provide temporary relief, or major surgical intervention. Neither has proven to provide suitable long-term outcomes. Emerging strategies focus on injectable biomaterials to provide structural support and facilitate tissue repair, although they are still largely experimental and face several limitations, including limited integration with native tissue. Moreover, the implant formation mechanism may be depth-limited (light curing) or time-constrained (self-curing). Aim: The objective of this research is to demonstrate a new option to restore spinal function through the use of extracorporeal ultrasound to remotely trigger in situ implant formation on demand, such that the clinician can control the process with the timing and location of their choosing. The system concept centers around an implant precursor material consisting of an anionic polysaccharide matrix seeded with thermally sensitive liposomes. Ultrasound-mediated heating on the order of 3-5 degrees above normal body temperature triggers the release of crosslinking species from the liposomes, thereby initiating hydrogel formation. Methods: Candidate polysaccharide and liposome formulations were evaluated for their injectability, loading efficiency, and post-gelation mechanical properties. Ultrasound parameters (frequency, pressure, duty cycle) were optimized for targeted heating efficiency. Techniques for treatment process monitoring and control were independently investigated using thermometry and acoustic cavitation emissions. The material constructs and ultrasound protocols were used together in a series of proof-of-concept experiments using ex vivo bovine IVD specimens, with biomechanical analysis across three states: intact, degenerated, and after ultrasound-triggered implant formation. Results: Extensive testing revealed an optimized implant precursor material consisting of sodium alginate (1.5 wt/v%) seeded with calcium-loaded liposomes (157±9 nm) to enable hyperthermia-triggered release and glass microspheres (6 wt/v%) to ensure preferential ultrasound absorption for safe heating. No significant difference was found between hydrogels heated with an incubator or ultrasound, suggesting comparable calcium release between both methods. Optimal ultrasound parameters for precursor gel heating were found to be 0.95 MHz, 1.6 MPa (peak negative), and 87% duty cycle. Automated treatment control using temperature or cavitation emission measurements both were successfully implemented, with cavitation being preferable for non-invasive implementation. Proof of concept experiments indicated partial restoration of biomechanical function in ex vivo bovine IVDs, with implant material well-integrated into the disc tissue, and without material herniation. Conclusion: We have demonstrated the feasibility of ultrasound-guided hydrogel gelation in situ. These results offer promise for treating spinal disc degeneration, with continued refinement of materials and protocols essential for achieving robust in-disc efficacy.

Biomechanical characterization of native NP tissue and the hydrogel was performed using a Mach-1 V500CSST mechanical testing system (MA009, Biomomentum, Montreal, Canada) fitted with a single-axis 10 N load cell (MA410, Biomomentum, Montreal, Canada), a quick connection adapter with 3.2 mm diameter dowel pin, and an acrylic confined compression chamber bounded at one end with a rigid, 316L sintered steel, porous (40 μl) platen (MA742, Biomomentum, Montreal, Canada). To calibrate the test system, the dowel pin was lowered into the confining chamber and brought into contact with the platen using displacement control at a speed of 0.02 mm/s until a tare load of 10 gf (0.0981 N) was reached. The position measurement was then zeroed, and the pin was removed.

A dissected disc was cut using a bandsaw at mid-height while frozen. A 3.2 mm diameter cross-section was then removed from the NP center using a sharp punch. A similarly shaped sample was also excised from the hydrogel. Then, a 1.5 mm thick aluminum plate containing a 3.2 mm diameter drill hole was stored at −20 ˚C for 20 minutes. The NP and hydrogel samples were inserted into this drill hole, and a microtome blade was used to shave each to 1.5 mm thickness by sliding along the top and bottom plate surfaces. To measure sample height, each was inserted until contact with the plate was made, and the rod was then brought into contact with the sample at a speed of 0.02 mm/s until a tare load of 10 gf (0.0981 N) was achieved since preliminary investigations indicated this was a good threshold for contact. Sample thickness was recorded as the distance between the zero position and the metal rod, according to manufacturer instructions (MA056-SOP06-D v3, Biomomentum, Montreal, Canada).

Before compression, samples underwent isometric swelling within the confined compression chamber to avoid sample over-hydration and pressurization of the test chamber. With the dowel pin still in place, the chamber was filled with 37 ˚C DPBS, and the samples were held in position for 1800 seconds (hydrogel) and 10800 seconds (NP) following preliminary investigations, which indicated these periods were sufficient for samples to reach equilibrium. Equilibrated samples were then subjected to a ramp test. Samples were compressed to 30 % (0.45 mm) since this captured the range of physiological strains experienced by the NP. The compressive strain rate was 0.1 % s-1 (0.0015 mm s-1) following a review of the literature, as low strain rates are necessary for water to egress from the material and through the plate during confined compression.