Bone morphogenetic protein-2 used in spinal fusion with spinal cord injury penetrates intrathecally and elicits a functional signaling cascade
The use of recombinant human bone morphogenetic protein-2 (rhBMP-2) and its indications for spinal fusion continue to be expanded with recent reports citing spinal trauma application. However, there are no data establishing the effects of rhBMP-2 on the injured spinal cord.
The purpose of this study was to evaluate the extent of bone morphogenetic protein (BMP)-specific intrathecal signaling after application to the spine at various time points after a spinal cord injury (SCI).
This is an in vivo rat study using a combination of the dorsal hemisection SCI and the posterolateral arthrodesis animal models.
Sixty-five female Sprague-Dawley rats underwent either a T9-T10 dorsal hemisection SCI (n=52) or laminectomy only (n=13). Spinal cord injury animals were further subdivided into four follow-up groups (n=13/group): 30 minutes, 24 hours, 7 days, and 21 days, at which time one of two secondary surgeries were performed: Eight rats per time point received either 43 microg of rhBMP-2 per side or sterile water control over T9-T11 on absorbable collagen sponges (ACSs). Animals were perfused after 24 hours, and spinal cords were immunohistochemically analyzed. Sections of the lesion were stained with BMP-specific pSmad 1, 5, 8 antibody and costained with cell-specific markers. pSmad-positive cells were then counted around the lesion. The remaining five rats (n=5/time point) had luciferase (blood spinal cord barrier [BSCB] permeability marker) injected through the jugular vein. Subsequently, spinal cords were collected and luciferase activity was quantified around the lesion and in the cervical samples (controls) using a luminometer.
After injury, a significant increase in the number of pSmad-positive cells was observed when rhBMP-2 was implanted at the 30-minute, 24-hour, and 7-day time points (p<.05). Costaining revealed BMP-specific signaling activation in neurons, glial cells, macrophages, and fibroblasts. Spinal cord permeability to luciferase was significantly increased at 30 minutes, 24 hours, and 7 days post lesion (p<.05). A significant linear regression was established between the extent of BSCB permeability and pSmad signaling (r(2)=0.66, p=.000).
Our results indicate that rhBMP-2 use around a spinal cord lesion elicits a robust signaling response within the spinal cord parenchyma. All CNS cell types and the invading fibroblasts are activated to the extent dependent on the integrity of the meningeal and BSCB barriers. Therefore, in the presence of a SCI and/or dural tear, rhBMP-2 diffuses intrathecally and activates a signaling cascade in all major CNS cell types, which may increase glial scarring and impact neurologic recovery.
Available from: Zhang Wen
- "Manual palpation is an easy and specific way for assessing rat postero-lateral spinal fusion , , , . 16 weeks after surgery, all rats were killed and the spines were collected and the segments from T12 (Thoracic) to sacrum were preserved. "
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ABSTRACT: Bone morphogenetic protein-2 (BMP-2) is a potent osteoinductive cytokine that plays a critical role in bone regeneration and repair. However, its distribution and side effects are major barriers to its success as therapeutic treatment. The improvement of therapy using collagen delivery matrices has been reported. To investigate a delivery system on postero-lateral spinal fusion, both engineered human BMP-2 with a collagen binding domain (CBD-BMP-2) and collagen scaffolds were developed and their combination was implanted into Sprague-Dawley (SD) rats to study Lumbar 4-5 (L4-L5) posterolateral spine fusion. We divided SD rats into three groups, the sham group (G1, n = 20), the collagen scaffold-treated group (G2, n = 20) and the BMP-2-loaded collagen scaffolds group (G3, n = 20). 16 weeks after surgery, the spines of the rats were evaluated by X-radiographs, high-resolution micro-computed tomography (micro-CT), manual palpation and hematoxylin and eosin (H&E) staining. The results showed that spine L4-L5 fusions occurred in G2(40%) and G3(100%) group, while results from the sham group were inconsistent. Moreover, G3 had better results than G2, including higher fusion efficiency (X score, G2 = 2.4±0.163, G3 = 3.0±0, p<0.05), higher bone mineral density (BMD, G2: 0.3337±0.0025g/cm3, G3: 0.4353±0.0234g/cm3. p<0.05) and more bone trabecular formation. The results demonstrated that with site-specific collagen binding domain, a dose of BMP-2 as low as 0.02mg CBD-BMP-2/cm3 collagen scaffold could enhance the posterolateral intertransverse process fusion in rats. It suggested that combination delivery could be an alternative in spine fusion with dramatically decreased side effects caused by high dose of BMP-2.
Available from: Dennis A. Kopf
- "When an autograft is harvested from the iliac crest, 33% of patients complain of chronic pain at the harvest site (Hoheinz, 2008). There have even been studies that found up to 60% of patients complain of pain 2 years post operatively (Dmitriev, 2010). Also patients with low bone density or other types of degenerative bone diseases are often not qualified to have an autograft. "
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– The purpose of this paper is to discover best practices for selling stem cell based biologics and ensuring proper sales force alignment in the biomedical device industry.
– This research is based on an immersion into the industry as well as several formal, semi-structured interviews and dozens of informal interviews of surgeons, medical staff and medical device salespersons and managers. Data were also collected and analyzed from wipricepoint.org. The factors analyzed were the number of discharges, average charge per procedure, median age, male/female patient ratio and total hospital charges per year.
– Secondary data can augment primary data collection to determine the most lucrative markets for salespersons to target their efforts. In addition, the data when combined with sales force specific data can help optimize sales force alignment. Insights into the industry are also given such as how to overcome objections to the use of stem cell based biologics for spinal surgeries.
– Much of the findings are specific to only one industry (medical device sales). However, we do present a generalized process for analyzing a key source of secondary data that could be beneficial to any hospital-serving industry.
– Within the medical equipment industries, approximately 58 per cent of sales territories were either too large or too small (Zoltners and Lorimer, 2000). This paper shows how secondary data sources can be obtained and analyzed to better focus sales force effort.
Available from: 126.96.36.199
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ABSTRACT: This paper analyses the performance of the downlink transmit diversity techniques specified in the standard of the UTRA FDD mode. The Downlink DPCH can use either closed loop or open loop transmit diversity (space time block coding based transmit diversity) or closed loop transmit diversity to improve performance. In order to evaluate how these techniques work, a simulator of the physical layer of UMTS has been implemented in the C language. Simulation results show that the closed loop methods are the best way of getting diversity gain in radio environments with a low Doppler frequency, especially mode 2. Nevertheless, when a correct channel knowledge (high Doppler frequency) does not exist, the open loop transmit diversity mode is the best option.
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