This preclinical study indicates that delivering TNF-alpha inhibitors by means of a locally administered polymeric formulation provides long-lasting analgesia in an inflammatory neuropathic pain model.

Recombinant human Bone Morphogenetic Protein-2 (rhBMP-2) is currently employed as an autograft replacement for spinal fusion. The morphogen is incorporated onto its carrier, an absorbable collagen sponge (ACS), in the operating room. Although the effectiveness of the rhBMP-2/ ACS implant in stimulating bone formation in human subjects has now been well established, further investigations of its use are necessary to deepen our understanding of its performance. The objective of the present study was to determine whether fluid released from the rhBMP-2/ACS implant could induce bone growth in tissue sites away from the implant site. We first measured the amount of protein in the fluid released from the rhBMP-2-soaked ACS during intraoperative handling. Variables included soak time and degree of compression. In the compression group that most closely approximated intraoperative conditions, more than 95% of the rhBMP-2 protein was retained by the ACS following a 15-min. soak time. This in vitro study was followed by an in vivo ectopic implant experiment using rat and rabbit models. The animal investigation compared the amount of bone induced by rhBMP-2 solution alone versus the de novo bone formation induced by rhBMP-2/ACS implants with varying concentrations of rhBMP-2. No ossicles were found at the sites where rhBMP-2 solution was injected in either animal species. Twenty-two of the 24 subcutaneous sites in the rats implanted with the rhBMP-2/ACS constructs displayed the presence of the typical 4-and 12-week ossicle. There were no noticeable differences in the size and shape of the ossicles after 4 and 12 weeks. There was a greater percentage of implant sites without ossicles in the rabbits, compared to the rats. ß

Object In this study the authors tested the osteoinductive potential of recombinant human bone morphogenetic protein–2 (rhBMP-2) when combined with each of three commercially available contrast media (Conray, Omniscan, and Optiray). Methods Initial in vitro and cadaver tests verified the feasibility of using contrast media to visualize absorbable collagen sponge implants containing rhBMP-2 on fluoroscopic radiographic images. For the feasibility studies, lyophilized rhBMP-2 was prepared for injection by reconstitution with contrast media instead of sterile water. For the in vivo study, samples of an rhBMP-2 stock solution were diluted to 0.1 mg/ml by using three contrast media. In each sample, the final solution consisted of 97% contrast medium by volume. Recombinant human bone morphogenetic protein–2 diluted with sterile water for injection was used as a positive control. The rhBMP-2 solutions were applied to 0.5-cm3 collagen sponges and implanted subcutaneously on the thoracic cavity of athymic rats. At 4 weeks, the rats were killed, and the implants were removed. The explants were graded for degree of bone formation by using manual palpation and radiographic and histological assessments. Conclusions By all methods of evaluation used, rhBMP-2 diluted with Omniscan was equivalent to rhBMP-2 diluted with sterile water in inducing bone formation. Both Conray and Optiray were shown to inhibit the osteoinductive potential of rhBMP-2.

OBJECTIVE It has been hypothesized that the recombinant human bone morphogenetic protein-2 (rhBMP-2) amplification of the host inflammatory response interacts with nerves in the spine and contributes to the occurrence of new, postoperative complaints of radiculitis. This in vivo rat study was conducted to assess the capacity for rhBMP-2/ACS (rhBMP-2 applied to absorbable collagen sponge [ACS]) to stimulate pain-associated behaviors in the rat chronic constriction injury (CCI) model. METHODS Rats were randomly assigned to one of 14 treatment groups. Half of the animals underwent a sham procedure in which the left sciatic nerve was exposed and manipulated but no ligature was placed (Sham cohort), while the remaining animals had chromic gut sutures tied around the sciatic nerve to induce CCI (CCI cohort). The following test articles were applied to the sciatic nerve in each cohort: saline alone, saline applied to ACS, 0.1 mg/ml rhBMP-2 applied to ACS, or 1.0 mg/ml rhBMP-2 applied to ACS. The ACS was either wrapped around the sciatic nerve or implanted adjacent to the nerve. Thermal withdrawal latency was assessed on Days 7, 14, 21, and 28 postoperatively. Isolated nerves from selected rats in each group were examined and assessed for histopathological changes on Days 3, 7, 14, and 28. RESULTS CCI produced a significant pain behavioral response for all treatment groups at all time points. In the Sham cohort, 0.1 mg/ml rhBMP-2/ACS wrapped around the nerve (WRP) decreased thermal withdrawal on Day 28, and 1.0 mg/ml rhBMP-2/ACS placed adjacent to the nerve (ADJ) decreased thermal withdrawal on Days 21 and 28. Conversely, in the CCI cohort, 0.1 mg/ml rhBMP-2/ACS ADJ increased thermal withdrawal latencies on Day 7; 1.0 mg/ml rhBMP-2/ACS ADJ increased thermal withdrawal latencies on Day 7; and 1.0 mg/ml rhBMP-2/ACS WRP increased thermal withdrawal on Days 7 and 14. Histologically, the effect of rhBMP-2 on nerve inflammation was unclear, as inflammatory cell infiltration was similar in the rhBMP-2/ACS and saline/ACS groups. rhBMP-2 was variably associated with bone formation within the epineurium at 14 days, and more prevalently at 28 days, with no clear relationship between dose or ACS positioning. CONCLUSIONS In this study, rhBMP-2/ACS did not appear to induce pain independent of grossly visible ectopic bone formation. At the earliest time points, rhBMP-2 appeared to have a neuroprotective effect as evidenced by decreased pain exhibited by the rhBMP-2–treated animals in the CCI cohort, but this effect diminished over time, and by Day 28, the pain behavioral responses in the rhBMP-2–treated group were comparable to those in the group in which saline was applied to the nerve. In the Sham cohort, there was a dose-independent induction of pain at later time points, presumably due to new bone formation mechanically irritating the nerve. Histological examination revealed nerve lesions that appeared to be caused by mechanical trauma associated with surgical manipulation of the nerve during placement of the ACS and/or CCI sutures.