Longitudinal in vivo monitoring of callus remodeling in BMP-7- and Zoledronate-treated fractures.

Pharmacological interventions that combine pro-anabolic and anti-catabolic drugs to treat recalcitrant fractures have shown remarkable efficacy in augmenting the regenerative response. Specifically, in rodent models of fracture repair, treatment with BMP-7 and Zoledronate (ZA) has almost uniformally resulted in complete union. However, delayed remodeling may be problematic for ZA-treated fractures. The increase in newly formed bone is substantial but if translated in humans, delayed remodeling may delay functional recovery. Our objective was to determine if, and to what extent, bone morphogenetic protein (BMP) (in synergistically administered BMP-7 + ZA) can modulate the delayed hard callus remodeling caused by ZA. Callus remodeling in BMP-7-only and BMP-7 + ZA-treated osteotomies were monitored using in vivo µCT to follow the progression of healing at 6-week intervals over 24 weeks in an open femoral fracture rat model. None of the groups recovered baseline cortical bone volumes within 24 weeks post-osteotomy. Treatment prolonged the remodeling phase but the kinetics of remodeling appeared to differ between BMP and BMP + ZA groups. However, the mechanical characteristics were largely restored. Callus/bone volumes in BMP-only treated fractures peaked as early as week 3 suggesting that remodeling is stimulated prematurely. However, this rate of remodeling was not maintained as BMP-7 was found to exhibit negligible changes in callus/bone volumes between weeks 6 and 18, whereas declines in callus/bone volumes were present at these time points in the BMP-7 + ZA group. Our findings suggest that inclusion of ZA as an anti-catabolic agent may not be detrimental to the regenerative process despite a prolonged remodeling phase.

Enhancement of the effects of intermittent parathyroid hormone (1-34) by bone morphogenetic protein in a rat femoral open fracture model.

BACKGROUND: Nonunion in cases of open fracture is common. Both bone morphogenetic protein 2 (BMP-2) and parathyroid hormone (PTH) have been used to enhance bone healing. We investigated the combination of BMP-2 and PTH and examined the effects on a rat model of open femoral fractures. METHODS: Group I (n = 11) was implanted with control carrier. Group II (n = 12) was implanted with carrier containing 1 µg of recombinant human BMP-2 (rhBMP-2). Group III (n = 12) was implanted with carrier alone, followed by injections of PTH 1-34. Group IV (n = 11) was implanted with carrier containing 1 µg of rhBMP-2, followed by injections of PTH 1-34. Group V (n = 11) was implanted with carrier containing 10 µg of rhBMP-2. Group VI (n = 11) was implanted with carrier containing 10 µg of rhBMP-2, followed by injections of PTH 1-34. Rats were euthanized after 8 weeks, and their fractured femurs were explanted and assessed by manual palpation, radiographs, micro-computerized tomography, and histological analysis. RESULTS: Manual palpation tests showed that the fusion rates of groups III (66.7%), IV (63.6%), V (81.8%), and VI (81.8%) were considerably higher than those of group I. Groups V and VI had higher radiographic scores compared to group I. Micro-CT analysis revealed enhanced bone marrow density expressed as bone volume/tissue volume in groups V (61.88 ± 3.16%) and VI (71.14 ± 3.89%) versus group I (58.26 ± 1.86%). A histological analysis indicated that group VI had enhanced remodeling. CONCLUSION: The combination of abundant rhBMP-2 and PTH enhanced bone healing and remodeling of newly formed bone in a rat femoral open fracture model.

BMP-2 delivered via sucrose acetate isobutyrate (SAIB) improves bone repair in a rat open fracture model.

Human bone morphogenetic proteins (BMPs) are an alternative to bone graft for the treatment of high-energy open fractures. The standard delivery system for BMP-2 is a porous collagen sponge, but we have previously found that the biocompatible, high viscosity carrier, Sucrose acetate isobutyrate (SAIB) is an effective and potentially less invasive alternative. The efficacy of SAIB as a BMP-2 delivery system was examined in an open fracture model featuring a femoral osteotomy with periosteal stripping in 9-week-old male Sprague Dawley rats. SAIB containing BMP-2 (SAIB/BMP-2) was delivered into the fracture site during surgery and an additional group was further co-treated with zoledronic acid and hydroxyapatite nanoparticles (SAIB/BMP-2/HA/ZA). These were compared to untreated fractures and SAIB carrier alone (negative controls), and BMP-2 loaded collagen sponge (positive control). The rate of radiographic union and the biomechanical properties of the healed fractures were compared after 6-week. Untreated and SAIB-treated fractures showed poor repair, with 53% and 64%, respectively, not bridged at 6 week. In contrast, collagen/BMP-2, SAIB/BMP-2, and SAIB/BMP-2/HA/ZA showed significantly increased union (100%, 100%, and 94%, respectively, p < 0.05). Four-point bend testing revealed that collagen/BMP-2 and SAIB/BMP-2/HA/ZA restored the strength of fractured femora to that of intact femora by 6 week, whereas untreated and SAIB remained less than intact controls by 60% and 67%, respectively (p < 0.05). Overall, the SAIB/BMP-2/HA/ZA formulation was comparable to BMP-2 infused collagen sponge in terms of promoting open fractures repair, but with the additional potential for less invasive delivery. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1168-1176, 2016.

Negative pressure wound therapy reduces the effectiveness of traditional local antibiotic depot in a large complex musculoskeletal wound animal model.

OBJECTIVES: Negative pressure wound therapy (NPWT) has been used to help manage open wounds. Surgeons also often use local antibiotic depot as adjunctive therapy in an effort to reduce infection rates. These 2 techniques have been reported to be used in conjunction, but there are little data to support this practice. We sought to compare the contamination levels of wounds treated with the commonly used antibiotic bead pouch technique to wounds that received both antibiotic beads and NWPT. METHODS: The effectiveness of a bead pouch was compared with antibiotic beads with NPWT. The anterior compartment and proximal tibia of goats were injured and inoculated with Staphylococcus aureus. Six hours later, the wounds were debrided and the animals were assigned to a group; the bacteria level was quantified immediately before and after initial debridement and 2 days after treatment. RESULTS: The wounds in the antibiotic bead pouch group had 6-fold less bacteria than the augmented NPWT group, 11 ± 2% versus 67 ± 11% of baseline values, respectively (P = 0.01). As expected, high levels of the antibiotic were consistently recovered from the augmented NPWT effluent samples at all time points. CONCLUSIONS: NPWT reduces the effectiveness of local antibiotic depot. These results can provide surgeons with the information to personalize the adjunctive therapies to individual patients, with the degree of difficulty in managing the wound and concern for infection being the 2 variables dictating treatment.

Antibiotic-impregnated calcium sulfate use in combat-related open fractures.

This article presents our experience with the use of antibiotic-impregnated calcium sulfate in the management of comminuted open fractures with a bony defect caused by combat-related blast injuries and high-energy wounds. Calcium sulfate was used 19 times in 15 patients (17 fractures) as a bone graft substitute and a carrier for antibiotics. The anatomic sites of the graft were as follows: 6 calcanei, 1 midfoot, 1 metatarsal, 5 tibiae, 3 femorae, and 1 humerus. The average number of procedures prior to grafting was 6.2 (range, 2-10; median, 6) with grafting performed at an average 28 days after injury (range, 9-194 days; median, 14 days). Average radiographic follow-up of 12 fractures not requiring repeat grafting or amputation was 8.5 months (range 1-19 months; median, 7 months), and all of these fractures demonstrated clinical and radiographic evidence of fracture healing and consolidation. Four patients subsequently underwent 5 transtibial amputations: 2 for persistent infection, 1 when the patient changed his mind against limb salvage acutely, and 2 for severe neurogenic pain. Including the 2 amputations for persistent infection, 4 patients (22.2%) required further surgical management of infection. Three patients (17.6%) subsequently developed heterotopic ossification at the graft site, which required surgical excision. Antibiotic-impregnated calcium sulfate is effective in treating severe, contaminated open fractures by reducing infection and assisting with fracture union.

Prospective, randomized, double-blind study comparing single-agent antibiotic therapy, ciprofloxacin, to combination antibiotic therapy in open fracture wounds.

OBJECTIVE: The purpose of this study was to compare the efficacy of a single agent, ciprofloxacin, with that of combination antibiotic therapy consisting of cefamandole and gentamicin in all types of open fracture wounds. STUDY DESIGN: A prospective double-blind randomized clinical trial. SETTING: A Level 1 trauma center. PATIENTS: One hundred ninety-five consecutive patients with 203 open fractures were enrolled over a twenty-month period. Twenty-nine fractures from low-velocity gunshot wounds were excluded, and three other patients were excluded because of protocol violations. Our final number of patients were 163, with 171 open fractures. MAIN OUTCOME MEASUREMENT: The infection rates for Type I and Type II open fractures for both antibiotic groups were calculated. The infection rate of Type III open fractures for both antibiotic groups was also calculated. Chi-square analysis with Yates correction was used to assess statistical significance of two treatment groups. RESULTS: The infection rate for Types I and II open fractures in the ciprofloxacin group was 5.8 percent and 6 percent for the cefamandole/gentamicin group (p = 1.000). The infection rate for Type III open fractures for the ciprofloxacin group was 31 percent (8 of 26) versus 7.7 percent (2 of 26) for the cefamandole/gentamicin group (p = 0.079). There were no statistically significant differences in infection rate between the group treated with ciprofloxacin and that treated with cefamandole/gentamicin for Types I and II open fracture wounds. However, there appeared to be a high failure rate for the ciprofloxacin Type III open fracture group, with patients being 5.33 times more likely to become infected than those in the combination therapy group. Although this difference was not statistically significant, possibly because of the small sample size, there was a definite trend toward statistical significance. CONCLUSION: Single-agent antibiotic therapy with ciprofloxacin is effective in treatment of Type I and Type II open fracture wounds. However, on the basis of our results, we cannot recommend ciprofloxacin alone for Type III wounds. Possibly one can use fluoroquinolones in combination therapy, specifically as an alternate to an aminoglycoside.

[Application of "Aekol" preparation for combined treatment of open injuries]. / Primenenie preparata "Aekol" v kompleksnom lechenii otkrytykh povrezhdenii.

Therapeutic effect of "Aekol" preparation (artificial sea-buckthorn oil) has been studied in the process of treatment of 41 victims and patients with open injuries of limb segments, pyo-necrotic complications of skeletal trauma, investing tissue necrosis following cavitary and cutaneoplastic operative interventions, tropic disturbances of investing tissue integrity. "Aeko" preparation efficiency has been compared with the efficiency of prototype preparation (natural sea-buckthorn oil) and with the efficiency of remedies, traditionally applied for the II phase of the wound process. On the basis of clinical observations, wound surface planimetry, investigation of wound surface bioptats and study of dynamics of some biochemical components in the blood serum in the process of wound healing the authors concluded that the clinical efficiency of "Aekol" preparation in open injure treatment is comparable with the efficiency of natural sea-buckthorn oil and considerably exceeds the efficiency of the traditional would healing remedies.