Ben Goss

Combined VEGF and PDGF Treatment Reduces Secondary Degeneration after Spinal Cord Injury

Trauma to the spinal cord creates an initial physical injury damaging neurons, glia, and blood vessels, which then induces a prolonged inflammatory response, leading to secondary degeneration of spinal cord tissue, and further loss of neurons and glia surrounding the initial site of injury. Angiogenesis is a critical step in tissue repair, but in the injured spinal cord angiogenesis fails; blood vessels formed initially later regress. Stabilizing the angiogenic response is therefore a potential target to improve recovery after spinal cord injury (SCI). Vascular endothelial growth factor (VEGF) can initiate angiogenesis, but cannot sustain blood vessel maturation. Platelet-derived growth factor (PDGF) can promote blood vessel stability and maturation. We therefore investigated a combined application of VEGF and PDGF as treatment for traumatic spinal cord injury, with the aim to reduce secondary degeneration by promotion of angiogenesis. Immediately after hemisection of the spinal cord in the rat we delivered VEGF and PDGF and to the injury site. One and 3 months later the size of the lesion was significantly smaller in the treated group compared to controls, and there was significantly reduced gliosis surrounding the lesion. There was no significant effect of the treatment on blood vessel density, although there was a significant reduction in the numbers of macrophages/microglia surrounding the lesion, and a shift in the distribution of morphological and immunological phenotypes of these inflammatory cells. VEGF and PDGF delivered singly exacerbated secondary degeneration, increasing the size of the lesion cavity. These results demonstrate a novel therapeutic intervention for SCI, and reveal an unanticipated synergy for these growth factors whereby they modulated inflammatory processes and created a microenvironment conducive to axon preservation/sprouting.

In vivo temperature profile of intervertebral discs and vertebral endplates during vertebroplasty - An experimental study in sheep

Study Design. Experimental study of temperature profiles during vertebroplasty. Objectives. To define accurate temperature profiles during vertebroplasty in an in vivo animal model. Summary of Background Data. Controversy still exists whether vertebroplasty achieves its analgesic effect by stabilizing fracture fragments or due to thermal damage of sensory nerves inside the vertebral body. Furthermore, the energy release during cement polymerization may cause thermal injury to the spinal cord or intervertebral discs. Methods. A total of 4.0 mL PMMA was injected into three lumbar vertebrae of four skeletally mature mixed-bred ewes. Nine separate K-type thermocouples were placed into 12 vertebrae and their adjacent intervertebral discs. Temperature changes were recorded continuously before, during, and after the injection. Results. The highest peak temperatures were measured at the cranial endplate (mean 42.4 ± 8.8 C) and in the center of the vertebral body (mean 43.3 ± 6.9 C). Temperatures stayed above 40 C for approximately 2.5 minutes. Peak temperatures in the discs and at the dorsal wall (closest to spinal cord) did not exceed 41 C and 47 C and stayed above 40 C for approximately 1.5 minutes. Conclusions. The intervertebral discs and the spinal cord do not seem to be in danger of thermal damage during vertebroplasty. The measured energy does not seem to be sufficient for the palliative effect achieved by vertebroplasty.

Maintenance of segmental lordosis and disk height in stand-alone and instrumented extreme lateral interbody fusion (XLIF).

Study Design: A prospective single-surgeon nonrandomized clinical study. Objective: To evaluate the radiographic and clinical outcomes, by fixation type, in extreme lateral interbody fusion (XLIF) patients and provide an algorithm for determining patients suitable for stand-alone XLIF. Summary of Background Data: XLIF may be supplemented with pedicle screw fixation, however, since stabilizing structures remain intact, it is suggested that stand-alone XLIF can be used for certain indications. This eliminates the associated morbidity, though subsidence rates may be elevated, potentially minimizing the clinical benefits. Materials and Methods: A fixation algorithm was developed after evaluation of patient outcomes from the surgeon’s first 30 cases. This algorithm was used prospectively for 40 subsequent patients to determine the requirement for supplemental fixation. Preoperative, postoperative, and 12-month follow-up computed tomography scans were measured for segmental and global lumbar lordosis and posterior disk height. Clinical outcome measures included back and leg pain (visual analogue scale), Oswestry Disability Index (ODI), and SF-36 physical and mental component scores (PCS and MCS). Results: Preoperatively to 12-month follow-up there were increases in segmental lordosis (7.9–9.4 degrees, P=0.0497), lumbar lordosis (48.8–55.2 degrees, P=0.0328), and disk height (3.7–5.5 mm, P=0.0018); there were also improvements in back (58.6%) and leg pain (60.0%), ODI (44.4%), PCS (56.7%), and MCS (16.1%) for stand-alone XLIF. For instrumented XLIF, segmental lordosis (7.6–10.5 degrees, P=0.0120) and disk height (3.5–5.6 mm, P<0.001) increased, while lumbar lordosis decreased (51.1–45.8 degrees, P=0.2560). Back (49.8%) and leg pain (30.8%), ODI (32.3%), PCS (37.4%), and MCS (2.0%) were all improved. Subsidence occurred in 3 (7.5%) stand-alone patients. Conclusions: The XLIF treatment fixation algorithm provided a clinical pathway to select suitable patients for stand-alone XLIF. These patients achieved positive clinical outcomes, satisfactory fusion rates, with sustained correction of lordosis and restoration of disk height.

Catalyst residue effects on the heterogeneous oxidation of polypropylene

The chemiluminescence (CL) curves in oxygen from polypropylene with a residual Ziegler-Natta catalyst Titanium concentration ranging from 0.2 to 4.1 ppm were measured from 100 to 150 degrees Celsius and it was found that the intensity of CL increased and the time taken to reach the maximum CL intensity decreased with [Ti]. The temperature dependence of the time to maximum CL intensity showed an apparent activation energy, Ea, of 88.1±0.6 kJ/mol that was independent of [Ti] but the pre-exponential factor, A′, decreased with increasing [Ti] according to a power law: A′=4.7×10−8[Ti]−0.3. This has been interpreted as reflecting the power law dependence of [Ti]−0.33 for the distance between residual particles of catalyst as sites for the initiation of heterogeneous oxidation. This has been tested by stochastic modelling of the spreading of oxidation for a range of volume fractions, p0, of infectious sites. This modelling allows pseudo-CL profiles to be constructed over the temperature range 100–150 degrees Celsius. The modelling has been restricted to p0 values equivalent to higher initial [Ti] but the results show that Ea is independent of [Ti] and A′ shows a power-law dependence of [Ti]−0.29 consistent with the experimental data.

Formation of blood clot on biomaterial implants influences bone healing.

The first step in bone healing is forming a blood clot at injured bones. During bone implantation, biomaterials unavoidably come into direct contact with blood, leading to a blood clot formation on its surface prior to bone regeneration. Despite both situations being similar in forming a blood clot at the defect site, most research in bone tissue engineering virtually ignores the important role of a blood clot in supporting healing. Dental implantology has long demonstrated that the fibrin structure and cellular content of a peri-implant clot can greatly affect osteoconduction and de novo bone formation on implant surfaces. This article reviews the formation of a blood clot during bone healing in relation to the use of platelet-rich plasma (PRP) gels. It is implicated that PRP gels are dramatically altered from a normal clot in healing, resulting in conflicting effect on bone regeneration. These results indicate that the effect of clots on bone regeneration depends on how the clots are formed. Factors that influence blood clot structure and properties in relation to bone healing are also highlighted. Such knowledge is essential for developing strategies to optimally control blood clot formation, which ultimately alter the healing microenvironment of bone. Of particular interest are modification of surface chemistry of biomaterials, which displays functional groups at varied composition for the purpose of tailoring blood coagulation activation, resultant clot fibrin architecture, rigidity, susceptibility to lysis, and growth factor release. This opens new scope of in situ blood clot modification as a promising approach in accelerating and controlling bone regeneration.

Diagnosis and Prognosis of Traumatic Spinal Cord Injury

Despite promising advances in basic spinal cord repair research, no effective therapy resulting in major neurological or functional recovery after traumatic spinal cord injury (tSCI) is available to date. The neurological examination according to the International Standards for Neurological and Functional Classification of Spinal Cord Injury Patients (International Standards) has become the cornerstone in the assessment of the severity and level of the injury. Based on parameters from the International Standards, physicians are able to inform patients about the predicted long-term outcomes, including the ability to walk, with high accuracy. In those patients who cannot participate in a reliable physical neurological examination, magnetic resonance imaging and electrophysiological examinations may provide useful diagnostic and prognostic information. As clinical research on this topic continues, the prognostic value of the reviewed diagnostic assessments will become more accurate in the near future. These advances will provide useful information for physicians to counsel tSCI patients and their families during the catastrophic initial phase after the injury.

Modelling of infectious spreading in heterogeneous polymer oxidation II. Refinement of stochastic model and calibration using chemiluminescence of polypropylene

In the stochastic model for infectious spreading of oxidation in a polymer, the conventional view of a homogeneously oxidising polymer with associated rate parameters is replaced by a system consisting of localized zones of oxidation in a continuous unoxidised substrate (a 3-dimensional matrix) with the rate of degradation controlled by the probability of passing the infection to an adjacent site, and the infectious lifetime of the site. The populations in the epidemiological model for spreading of oxidation, p(i) (the infectious, oxidising fraction), p(r) (the remaining, unoxidised fraction) and P-d (the dead or oxidised fraction) are calculated for a particular site. Oxidation-time profiles are determined by calculating the sum of the component fractions over the entire matrix volume for different activities (i.e. temperatures). Profiles of the infectious fraction, p(i), at different activities were found to show features of an accumulating hydroperoxide fraction whereas the true infectious fraction should be more correctly represented by the reactive fraction of the hydroperoxides, p(i)*, at a particular temperature. This model has been tested by comparison with the reactive hydroperoxide profile as determined by chemiluminescence of polypropylene doped with 9,10-diphenyl anthracene to yield the infectious spreading parameters, their temperature dependence, as well as the profiles for the diffusion of the infectious species

Clinical results and limitations of indirect decompression in spinal stenosis with laterally implanted interbody cages: results from a prospective cohort study

PurposeThe lateral approach for anterior interbody fusion allows placement of a large footprint intervertebral spacer to indirectly decompress the neural elements through disc height restoration and resultant soft tissue changes. However, it is not well understood under what circumstances indirect decompression in lateral approach surgery is sufficient. This report aimed to evaluate clinical scenarios where indirect decompression was and was not sufficient in symptom resolution when using lateral interbody fusion.MethodsA prospective study was undertaken of 122 consecutive patients treated with lateral interbody fusion without direct decompression. Pre- and postoperative symptomatology was assessed to evaluate the extent of neural decompression following implantation with a lateral polyetheretherketone spacer. Failure to improve or resolve preoperative radicular pain was considered a failure of indirect decompression and indicated these patients for additional posterior decompressive surgery.ResultsUnplanned second stage decompression was required in 11 patients. Of these patients, 7/11 early in this series had pathology that was underappreciated including spondylolisthesis from high grade facet arthropathy with instability (3), bony lateral recess stenosis (3) and both spondylolisthesis/stenosis (1). Three patients had iatrogenic leg pain through cage misplacement. There was one failure of indirect decompression that could not be explained through retrospective analysis of the patient’s record.ConclusionIndirect decompression clearly has a role in minimizing the amount of surgery that is required. However, it is important to consider the circumstances where this technique may be effective and preoperative considerations that may improve patient selection.

Indirect foraminal decompression is independent of metabolically active facet arthropathy in extreme lateral interbody fusion.

Study Design. Retrospective analysis of prospectively collected, nonrandomized radiographical data. Objective. To examine the relationship between the presence of preoperative metabolically active facet arthropathy (FA) and the amount of indirect foraminal decompression gained after extreme lateral interbody fusion (XLIF). Summary of Background Data. Although evidence of significant radiographical indirect decompression after XLIF has been shown, the relationship between the extent of indirect decompression and the presence of potentially attenuating, FA is yet to be studied. Methods. A prospective database of consecutive patients undergoing XLIF was retrospectively analyzed. Posterior disc height, foraminal height, and cross-sectional foraminal area were measured on computed tomographic scans obtained preoperatively and 2 days postoperatively. The selected radiographical parameters were examined with respect to the presence of FA based on preoperative computed tomographic and bone scans. Results. Fifty-two consecutive patients underwent 79 levels of XLIF without direct decompression. Average age was 66.4 years and 34 (65.4%) were females. Surgery resulted in significant increases in posterior disc height 3.0 to 5.7 mm (89.0% increase), P < 0.0001; foraminal height 1.4 to 1.7 cm (38.0% increase), P < 0.0001; and foraminal area 1.1 to 1.4 cm2 (45.1% increase), P < 0.0001. These increases were independent of the presence of metabolically active arthropathy. Conclusion. Significant indirect neural decompression is possible in XLIF, regardless of the presence of metabolically active FA. Level of Evidence: 3

Vascular endothelial growth factor and platelet derived growth factor modulates the glial response to a cortical stab injury.

Traumatic injury to the brain initiates an increase in astrocyte and microglial infiltration as part of an inflammatory response to injury. Increased astrogliosis around the injury impedes regeneration of axons through the injury, while activated microglia release inflammatory mediators. The persistent inflammatory response can lead to local progressive cell death. Modulating the astrocyte and microglial response to traumatic injury therefore has potential therapeutic benefit in brain repair. We examine the modulatory effect of a single bolus of vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) in combination on astrocytes and microglia to acute cerebral injury. A combination of VEGF and PDGF (20 pg) was injected into the striatum of adult male Sprague-Dawley rats. The effects of treatment were assessed by quantitative immunofluorescence microscopy analyzing astrocytes and microglia across the stab injury over time. Treatment delayed the onset of astrogliosis in the centre and edge of the stab injury up to day 5; however, increased astrogliosis at areas remote to the stab injury up to day 5 was observed. A persistent astrocytic response was observed in the centre and edge of the stab injury up to day 60. Treatment altered microglia cell morphology and numbers across the stab injury, with a decrease in ramified microglia, but an increase in activated and phagocytic microglia up to day 5 after stab injury. The increased microglial response from 10 until day 60 was comprised of the ramified morphology. Thus, VEGF and PDGF applied at the same time as a stab injury to the brain initially delayed the inflammatory response up to day 5 but evoked a persistent astrogliosis and microglial response up to 60 days.