Recombinant human bone morphogenetic protein-2 (rhBMP-2) can be used to enhance the repair of congenital or acquired bone pathologies when formulated in the appropriate carrier. Poly [D,L-(lactide-co-glycolide)] (PLGA) has been shown to be an effective carrier of rhBMP-2. We investigated several particle sizes PLGA and several doses of rhBMP-2 in a rat orthotopic model. We also investigated the effects of a fibrinolytic inhibitory agent, epsilon aminocaproic acid (EACA), on the healing response. Our data indicate that higher doses of rhBMP-2 resulted in increased failure torque (408 +/- 70 N-mm or 60% of the intact value) and higher incidence of union (100%). The induced bone in femurs treated with the smaller particle size PLGA achieved the greatest torsional stiffness and strength. The presence of rhBMP-2 was necessary for new bone to form, but the presence of EACA did not change these results; the use of the PLGA carrier appeared to increase bone strength and stiffness. In fact, with higher doses of rhBMP-2 in PLGA, the stiffness of the new bone was equal to that of intact controls (64 +/- 20 N-mm/deg [intact femurs] versus 45 +/- 10 N-mm/degree [medium dose in small PLGA], 61 +/- 17 N-mm/degree [high dose in small PLGA], and 36 +/- 11 N-mm/degree [medium dose in large PLGA]; P > .05). In conclusion, PLGA implanted with rhBMP-2 effectively aided in healing large segmental defects in rat femurs.
Objective: This study examined adherence to alert-based cues for plantar pressure offloading in patients with diabetic foot disease. Method and Design: Participants (n = 17) with in diabetic foot remission (history of neuropathic ulceration) were instructed to wear a smart insole system (the SurroSense Rx, Orpyx Medical Technologies Inc, Calgary, Canada) over a three-month period. This device is designed to cue offloading to manage unprotected sustained plantar pressures in an effort to prevent foot ulceration. A successful response to an alert was defined as pressure offloading, which occurred within 20 minutes of the alert onset. Patient adherence, defined as daily hours of device wear, was determined using sensor data and patient questionnaires. Changes in these parameters were assessed monthly. Results: Patients demonstrating increased adherence over the course of the study received more alerts (0.82 ± 0.31 alerts/hour) than patients whose adherence did not improve (0.36 ± 0.46 alerts/hour, P = .156). By the final stages of the study, participants who had received at least one alert every two hours were more adherent with offloading than participants who received fewer alerts (52.5 ± 4.1% vs 24.7 ± 22.4%, P = .043). Furthermore, duration of time from alert generation to successful offloading was significantly greater in the group receiving fewer alerts. This was measured in the third month with an effect size Cohen’s d = 1.739, P = .043. Conclusion: The results suggest a minimum number of alerts (one every two hours) is required for patients with diabetic neuropathy to optimally respond to offloading cues from a smart insole system.
In the current investigation, we report osseous regeneration in critical-size rat calvarial defects using recombinant human bone morphogenetic protein-2 (rhBMP-2) and novel delivery systems based on biomaterials. The novel systems combine rhBMP-2 with dry powder microparticles of poly(D,L-lactide-co-glycolide) (PLGA). The mixture of rhBMP-2 with PLGA microparticles is added to an aqueous solution of biopolymer to yield a semisolid paste. The biopolymers tested include autologous blood clot, hydroxypropyl methylcellulose, and sodium alginate cross-linked with calcium ion. Insoluble collageneous bone matrix was also studied as a control. Test articles were made at 0-, 10-, and 30-micrograms doses of rhBMP-2 and imiplanted in 8-mm-diameter rat calvarial defects (which will not heal if left untreated). The animals were examined 21 days after implantation by radiography, radiomorphometry, histology, and histomorphometry. All tested materials containing rhBMP-2 restored radiopacity and normal contouring to the calvarial defects. Samples without added rhBMP-2 yielded only soft tissue within the defects. Histology showed restoration of inner and outer bone tables plus marrow constituents. The PLGA microparticles were significantly resorbed at the 21-day time point. Although small differences between delivery systems were evident at 0- and 10-micrograms rhBMP-2 doses, all test articles performed essentially equivalently at the 30-micrograms dose. Thus, novel delivery systems for rhBMP-2 offer the promise of combining the intrinsic bioactivity of the osteoinductive protein with pharmaceutically acceptable biomaterials.
The purpose of this study was to measure bone-regenerative effects of recombinant human bone morphogenetic protein-2 (rhBMP-2) in rat calvarial critical-size defects (CSDs). CSDs (8 mm in diameter) were treated with either 1) 2.2 micrograms rhBMP-2 combined with insoluble collagenous bone matrix (ICBM), 2) 6.5 micrograms rhBMP-2 plus ICBM, 3) ICBM alone, or 4) demineralized bone matrix (DBM), for 7, 14, or 21 days. Multiple linear regression showed that rhBMP-2 had a significant time- and dose-dependent effect on bone regeneration (P < .05). After 7 days, new calcifying cartilage and remineralizing ICBM, with an occasional zone of new woven bone, was evident in defects treated with rhBMP-2/ICBM. By 14 days, both doses of rhBMP-2 reconstituted with ICBM had induced more bone formation than ICBM alone or DBM, and 6.5 micrograms was superior to 2.2 micrograms. There was no evidence of adverse cellular response. This study shows for the first time that rhBMP-2 could restore osseous form to a calvarial defect. In addition, osteoregeneration was accelerated by the higher dose of rhBMP-2.
Objective This study aims to assess the efficacy and safety of Gelesis100, a novel, nonsystemic, superabsorbent hydrogel to treat overweight or obesity. Methods The Gelesis Loss Of Weight (GLOW) study was a 24‐week, multicenter, randomized, double‐blind, placebo‐controlled study in patients with BMI ≥ 27 and ≤ 40 kg/m2 and fasting plasma glucose ≥ 90 and ≤ 145 mg/dL. The co‐primary end points were placebo‐adjusted weight loss (superiority and 3% margin super‐superiority) and at least 35% of patients in the Gelesis100 group achieving ≥ 5% weight loss. Results Gelesis100 treatment caused greater weight loss over placebo (6.4% vs. 4.4%, P = 0.0007), achieving 2.1% superiority but not 3% super‐superiority. Importantly, 59% of Gelesis100‐treated patients achieved weight loss of ≥ 5%, and 27% achieved ≥ 10% versus 42% and 15% in the placebo group, respectively. Gelesis100‐treated patients had twice the odds of achieving ≥ 5% and ≥ 10% weight loss versus placebo (adjusted OR: 2.0, P = 0.0008; OR: 2.1, P = 0.0107, respectively), with 5% responders having a mean weight loss of 10.2%. Patients with prediabetes or drug‐naive type 2 diabetes had six times the odds of achieving ≥ 10% weight loss. Gelesis100 treatment had no apparent increased safety risks. Conclusions Gelesis100 is a promising new nonsystemic therapy for overweight and obesity with a highly desirable safety and tolerability profile.
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