(190c) Evaluation of Novel Injectable Hydrogels | AIChE

(190c) Evaluation of Novel Injectable Hydrogels


Fussell, G. - Presenter, Synthes Spine
Lowman, A. M. - Presenter, Drexel University

Lower back pain is one of the most common medical problems in the world [1]. Approximately 75% of lower back pain cases are believed to be a result of degenerative disc disease (DDD)[2]. DDD is caused by damage to or dehydration of the nucleus pulposus, which reduces the hydrostatic pressure on the internal surface of the annulus fibrosis. This reduced hydrostatic pressure results in abnormal compressive stress on the intervertebral disc, potentially causing tears, cracks and fissures in the annular tissues after repeated loads. Back pain can develop as a result of nucleus tissue migrating through the annulus and impinging on nerve roots.

Currently, the major surgical treatment for degenerative disc disease is spinal fusion, but this causes loss of spinal mobility and increases stress on adjacent discs, accelerating degeneration of these joints. Total disc arthroplasty is emerging as a viable alternative to fusion because more spinal motion is retained. The Charité Artificial Disc (Johnson & Johnson) has been approved by the FDA for use as an intervertebral prosthesis. Other total disc replacement devices are currently under FDA study, including the ProDisc (Synthes Spine) and the Bryan Cervical Disc System (Medtronic Sofamor Danek).

Because this treatment involves highly invasive surgery, a promising alternative is the replacement of the nucleus pulposus alone. A synthetic nucleus replacement can be designed to recreate the biomechanical function of the intervertebral disc by transferring loads to the annulus, maintaining disc height, and preserving spinal motion. Devices currently being investigated are the Prosthetic Disc Nucleus (Raymedica), Newcleus (Zimmer, Spine), Hydrafil (Synthes Spine), Neudisc (Replication Medical Inc.), Aquarelle (Stryker Spine), Regain (EBI), and IPD (Dynamic Spine). While these pre-formed materials are promising, using an in situ forming nucleus replacement could have important clinical consequences, because it can be injected non-invasively using a small gage needle, minimizing soft tissue dissection and the risk of implant migration. The most common in situ forming nucleus pulposus replacements are self-curing elastomers such as silicon and polyurethane. Potential problems with in situ polymerization include heat generation and unreacted monomer.

Another way to achieve in situ gel formation is using a thermo-responsive polymer that forms a free flowing aqueous solution at ambient temperatures and a gel at body temperature. One such polymer is poly(N-isopropylacrylamide), or PNIPAAm. Aqueous solutions of PNIPAAm undergo a phase transformation at its lower critical solution temperature (LCST), which typically ranges between 29-34ºC. Below the LCST, the hydrophilic amide group dominates, while above the LCST, the hydrophobic isopropyl group dominates.

At physiological temperatures, PNIPAAm homopolymer gels hold little water and show poor elastic recovery. This work focuses on tailoring the swelling and mechanical properties of PNIPAAm gels by polymerizing NIPAAm in the presence of a small amount of poly(ethylene) glycol dimethacrylate (PEGDM), thereby creating PNIPAAm-PEGDM branched copolymers. A family of copolymers was created by varying the molecular weight of the PEGDM between 1000 and 8000 g/mol. High and low PEG content copolymers were synthesized by varying the relative proportions of NIPAAm and PEGDM. This study reports the effect that these parameters have on the water content, stiffness, and elasticity of PNIPAAm gels.

PEGDM (2000, 4600 and 8,000 g/mol) was synthesized from PEG according to the procedure outlined by Bryant et al[3]. PEGDM (1000 g/mol) was purchased from Polysciences. The PNIPAAm-PEGDM copolymers were synthesized by free radical polymerization in methanol at 65°C for 48 hours, initiated with 2,2'-Azobisisobutyronitrile, 98% (Sigma-Aldrich). 15 wt% polymer-water solutions were prepared from the dry polymer.

Small volumes of solution were heated to 37°C within a closed vial for 3 hours. The precipitated gels were then immersed in phosphate buffered saline (PBS) at 37°C. A set of gels were pulled at 0, 7, 14, 30, 60 and 90 days, weighed, and subsequently dried under vacuum. Time 0 refers to a set of gels that were weighed immediately after precipitation and never immersed in PBS. A mass swelling coefficient, q(t) was calculated by dividing the wet gel mass by its dry mass.

Unconfined uniaxial compression tests were performed on gel samples after 2, 7, 14, and 30 days immersion in vitro. The hydrogel samples were loaded in an Instron mechanical testing system and compressed at a strain rate of 100%?min-1 while submerged in a 37°C PBS bath. The compressive moduli at 10, 15, and 20% strain were approximated as the slope of the chord drawn between 5 and 15% strain, 10 and 20% strain, and 15 and 20% strain, respectively.

The ability for elastic recovery was evaluated using stress relaxation experiments, performed after 2, 7, 14, and 30 days immersion in PBS. Hydrogel samples were loaded in the Instron mechanical testing system and 20% compressive strain was applied and held for 1 hour while the gel was submerged in a 37°C PBS bath. The relaxation time constant for each copolymer was computed as the time needed to lower the stress from its original value to 1/e times its original value. The hydrogel height and diameter were also measured at 0, 30, and 55 minutes after unloading.

PNIPAAm-PEG (4600 and 8000 g/mol) had significantly higher mass swelling coefficients than the PNIPAAm homopolymer, the latter having the highest water content of all the copolymers. The high PEG content PNIPAAm-PEG (1000, 2000, and 4600 g/mol) met the minimum required unconfined compressive modulus of 50 kPa for the restoration of intervertebral disc stiffness[4]. The highest values for the relaxation time constant were seen for PNIPAAm-PEG (4600 and 8000 g/mol), indicating maximum elasticity.


1. Nachemson, A.L., Newest knowledge of low back pain. Clinical Orthopedics, 1992. 279: p. 8-20.

2. MedPro Month, 1998. VIII(1).

3. Bryant, S.J., T.T. Chowdhury, D.A. Lee, D.L. Bader, K.S. Anseth, Crosslinking density influences chondrocyte metabolism in dynamically loaded photocrosslinked poly(ethylene glycol) hydrogels. Annals of Biomedical Engineering, 2003. 32(3): p. 407-417.

4. Joshi, A.B., Mechanical behavior of the human lumbar intervertebral disc with polymeric hydrogel nucleus implant: An experimental and finite element study, in Materials science and engineering. February 2004, Drexel University: Philadelphia, PA.