Sean M. Mitchell

Hyperelastic “bone”: A highly versatile, growth factor–free, osteoregenerative, scalable, and surgically friendly biomaterial

A new, mechanically elastic biomaterial can be custom 3D-printed, is surgically friendly, and promotes robust bone regeneration. Building better bones What if we could create custom bone implants that would trigger their own replacement with real bone? Jakus and colleagues have done just this with a promising biomaterial that can be 3D-printed into many shapes and easily deployed in the operating room. Made mainly of hydroxyapatite and either polycaprolactone or poly(lactic-co-glycolic acid), this “hyperelastic bone” can be 3D-printed at up to 275 cm3/hour, the authors report. It also promoted bone growth in vitro, in mice and rats, and in a case study of skull repair in a rhesus macaque. Its effectiveness, fast, easy synthesis, and ease of use in surgery set it apart from many of the materials now available for bone repair. Despite substantial attention given to the development of osteoregenerative biomaterials, severe deficiencies remain in current products. These limitations include an inability to adequately, rapidly, and reproducibly regenerate new bone; high costs and limited manufacturing capacity; and lack of surgical ease of handling. To address these shortcomings, we generated a new, synthetic osteoregenerative biomaterial, hyperelastic “bone” (HB). HB, which is composed of 90 weight % (wt %) hydroxyapatite and 10 wt % polycaprolactone or poly(lactic-co-glycolic acid), could be rapidly three-dimensionally (3D) printed (up to 275 cm3/hour) from room temperature extruded liquid inks. The resulting 3D-printed HB exhibited elastic mechanical properties (~32 to 67% strain to failure, ~4 to 11 MPa elastic modulus), was highly absorbent (50% material porosity), supported cell viability and proliferation, and induced osteogenic differentiation of bone marrow–derived human mesenchymal stem cells cultured in vitro over 4 weeks without any osteo-inducing factors in the medium. We evaluated HB in vivo in a mouse subcutaneous implant model for material biocompatibility (7 and 35 days), in a rat posterolateral spinal fusion model for new bone formation (8 weeks), and in a large, non-human primate calvarial defect case study (4 weeks). HB did not elicit a negative immune response, became vascularized, quickly integrated with surrounding tissues, and rapidly ossified and supported new bone growth without the need for added biological factors.

Differences in bone mineral density of fixation points between lumbar cortical and traditional pedicle screws

BACKGROUND CONTEXT The use of a novel lumbar pedicle cortical bone trajectory (CBT) screw has recently gained popularity, allowing for a minimally invasive approach and potentially improved screw purchase. However, to date, no studies have identified the ideal patient population to utilize this technology. PURPOSE This study reports the bone mineral density (BMD) using Hounsfield units (HUs) along a CBT screw pathway. Patients with a greater difference in density of bone in the lumbar vertebrae between the fixation points of the CBT and traditional pedicle screw may be optimal candidates to realize the advantages of this technique. STUDY DESIGN/SETTING A cross-sectional observational anatomic study was carried out. PATIENT SAMPLE The sample comprised 180 randomly selected patients with lumbar computed tomography imaging from L1 to L5 spinal levels. OUTCOME MEASURES This study used computed tomography image-derived HUs as a metric for BMD. METHODS A total of 180 patients without previous lumbar surgery with computed tomography imaging of the lumbar spine met the inclusion criteria. Patients were chosen randomly from an institutional database based on age (evenly distributed by decade of life) and gender. Hounsfield units were measured at the expected end fixation point for both a cortical (superior/posterior portion of the vertebral body) and traditional pedicle trajectory (mid-vertebral body). RESULTS Hounsfield unit values measured at the end fixation point for the CBT screw were significantly greater than that of the traditional pedicle screw in all age groups. The relative difference in HU values significantly increased with each decade of age (p<.001) and caudal lumbar level (p<.001). In the osteoporotic group, as determined by well-established HU values, there was a significantly greater difference in the BMD of the CBT fixation point compared with the traditional trajectory (p=.048-<.001). CONCLUSIONS Bone mineral density as measured by HU values for the fixation point of the CBT screw is significantly greater than that of the traditional pedicle screw. This difference is even more pronounced when comparing osteoporotic and elderly patients to the general population. The data in this study suggest that the potential advantages from the CBT screw such as screw purchase may increase linearly with age and in osteoporotic patients.

Dioxin Exposure Impairs BMP-2-Mediated Spinal Fusion in a Rat Arthrodesis Model

BACKGROUND Cigarette smoking inhibits bone-healing and leads to increased rates of pseudarthrosis. However, the mechanisms behind these effects are controversial. Dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin)--a cigarette smoke constituent and potent activator of the aryl hydrocarbon receptor (Ahr)--negatively impacts bone quality and osteoblast differentiation. We hypothesized that activation of the Ahr by dioxin would inhibit bone morphogenetic protein (BMP)-2-mediated spinal fusion in a rat arthrodesis model. METHODS Female Long-Evans rats were pretreated with dioxin or vehicle in six weekly doses, followed by bilateral posterior lumbar spinal fusion across the L4-L5 transverse processes using recombinant human BMP (rhBMP)-2. Treatments continued until sacrifice at four weeks postoperatively. A third group was treated with dioxin for six weeks, followed by a recovery period of four elimination half-lives to assess the reversible effects of dioxin exposure on spinal fusion capacity. Bone formation and fusion capacity were evaluated using fusion scoring, radiography, micro-computed tomography, and histologic analysis. RESULTS Fusion scores for dioxin-treated and dioxin-recovery rats were significantly lower than those for controls. Although fusion rates were also significantly reduced in dioxin-treated animals relative to controls (50% versus 100%, respectively), rates were not significantly reduced in dioxin-recovery animals (80%). CONCLUSIONS Dioxin treatment significantly inhibited spinal fusion in a rat arthrodesis model, and a prolonged cessation of dioxin exposure facilitated only a partial recovery of bone-healing capacity. This finding indicates that, although the effects of dioxin are persistent, an extended recovery from exposure could potentially restore bone regeneration in vivo. CLINICAL RELEVANCE Development of a pharmacologic agent that reduces the adverse effects of cigarette smoke on bone-healing could prove useful to orthopaedic surgeons. Since dioxin and other similar cigarette smoke toxins exert their effects through Ahr pathway activation, the receptor represents a potential therapeutic target to improve spinal fusion rates in patients who smoke.

Intra-articular Vancomycin Powder Eliminates Methicillin-resistant S. aureus in a Rat Model of a Contaminated Intra-articular Implant

Background: Periprosthetic joint infection following hip and knee arthroplasty leads to poor outcomes and exorbitant costs. Topical vancomycin powder has been shown to decrease infection in many procedures such as spine surgery. The role of vancomycin powder in the setting of total joint arthroplasty remains undefined. Our aim was to evaluate the efficacy of intra-articular vancomycin powder in preventing infection in a rat model of a contaminated intra-articular implant. Methods: Thirty-two female Sprague-Dawley rats underwent knee arthrotomy and implantation of a femoral intramedullary wire with 1 mm of intra-articular communication. The knee joint was also inoculated with 1.5 × 107 colony forming units (CFU)/mL of methicillin-resistant Staphylococcus aureus (MRSA). Four treatment groups were studied: (1) no antibiotics (control), (2) preoperative systemic vancomycin, (3) intra-articular vancomycin powder, and (4) both systemic vancomycin and intra-articular vancomycin powder. The animals were killed on postoperative day 6, and distal femoral bone, joint capsule, and the implanted wire were harvested for bacteriologic analysis. Statistical analyses were performed using Wilcoxon rank sum and Fisher exact tests. Results: There were no postoperative deaths, wound complications, signs of vancomycin-related toxicity, or signs of systemic illness in any of the treatment groups. There were significantly fewer positive cultures in the group that received vancomycin powder in combination with systemic vancomycin compared with the group that received systemic vancomycin alone (bone: 0% versus 75% of 8, p = 0.007; Kirschner wire: 0% versus 63% of 8, p = 0.026; whole animal: 0% versus 88% of 8, p = 0.01). Only animals that received both vancomycin powder and systemic vancomycin showed evidence of complete elimination of bacterial contamination. Conclusions: In a rat model of a contaminated intra-articular implant, use of intra-articular vancomycin powder in combination with systemic vancomycin completely eliminated MRSA bacterial contamination. Animals treated with systemic vancomycin alone had persistent MRSA contamination. Clinical Relevance: This animal study presents data suggesting that the use of intra-articular vancomycin powder for reducing the risk of periprosthetic joint infections should be investigated further in clinical studies.

Mechanistic insight into the effects of Aryl Hydrocarbon Receptor activation on osteogenic differentiation

While inhibition of bone healing and increased rates of pseudarthrosis are known adverse outcomes associated with cigarette smoking, the underlying mechanisms by which this occurs are not well understood. Recent work has implicated the Aryl Hydrocarbon Receptor (Ahr) as one mediator of the anti-osteogenic effects of cigarette smoke (CS), which contains numerous toxic ligands for the Ahr. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin) is a high-affinity Ahr ligand frequently used to evaluate Ahr pathway activation. The purpose of this study was to elucidate the downstream mechanisms of dioxin action on bone regeneration and investigate Ahr antagonism as a potential therapeutic approach to mitigate the effects of dioxin on bone. Markers of osteogenic activity and differentiation were assessed in primary rat bone marrow stromal cells (BMSC) after exposure to dioxin, Ahr antagonists, or antagonist + dioxin. Four Ahr antagonists were evaluated: α-Naphthoflavone (ANF), resveratrol (Res), 3,3′-Diindolylmethane (DIM), and luteolin (Lut). Our results demonstrate that dioxin inhibited ALP activity, migratory capacity, and matrix mineralization, whereas co-treatment with each of the antagonists mitigated these effects. Dioxin also inhibited BMSC chemotaxis, while co-treatment with several antagonists partially rescued this effect. RNA and protein expression studies found that dioxin down-regulated numerous pro-osteogenic targets, whereas co-treatment with Ahr antagonists prevented these dioxin-induced expression changes to varying degrees. Our results suggest that dioxin adversely affects bone regeneration in a myriad of ways, many of which appear to be mediated by the Ahr. Our work suggests that the Ahr should be investigated as a therapeutic target to combat the adverse effects of CS on bone healing.

Does the level of cervical disc herniation surgery affect performance-based outcomes in national football league athletes?

Study Design. Retrospective cohort study. Objective. The aim of this study was to determine whether the level of a cervical disc herniation (CDH) procedure will uniquely impact performance-based outcomes in elite athletes of the National Football League (NFL). Summary of Background Data. Comparative assessments of postsurgical outcomes in NFL athletes with CDH at different levels are unknown. Further, the surgical decision-making for these types of injuries in professional football athletes remains controversial. Methods. NFL players with a CDH injury at a definitive cervical level were identified through a review of publicly available archives. Injuries were divided into upper- (C2-C4) and lower-level (C4-T1) CDH. The impact on player outcomes was determined by comparing return to play statistics and calculating a “Performance Score” for each player on the basis of pertinent statistical data, both before and after surgery. Results. A total of 40 NFL athletes met inclusion criteria. In the upper-level group, 10 of 15 (66.6%) players successfully returned to play an average of 44.6 games over 2.6 years. The lower-level cohort had 18 of 25 (72%) players return to play with an average of 44.1 games over 3.1 years. There was no significant difference in the rate of return to play (P = 0.71). Postsurgical performance scores of the upper and lower-level groups were 1.47 vs. 0.69 respectively, with no significant difference between these groups (P = 0.06). Adjacent segment disease requiring reoperation occurred in 10% of anterior cervical discectomy and fusion patients. In 50% of foraminotomy patients, a subsequent fusion was required. Conclusion. A uniquely high percentage of upper-level disc herniations develop in NFL athletes, and although CDH injuries present career threatening implications, an upper-level CDH does not preclude a player from successfully returning to play at a competitive level. In fact, these athletes showed comparable postsurgical performance to those athletes who underwent CDH procedures at lower cervical levels. Level of Evidence: 4

Accessibility of the Cervicothoracic Junction Through an Anterior Approach: An MRI-based Algorithm.

Study Design. Cross-sectional observational study. Objective. To formulate a reliable method and modality for preoperative planning and to determine the effects of height, body mass index (BMI), and age on accessibility to the upper thoracic vertebrae through an anterior cervical approach. Summary of Background Data. Various modalities have been proposed to determine the lowest spinal-level accessible through a traditional anterolateral cervical approach and the consequent need for manubriotomy. Past methods have routinely involved a variety of imaging studies such as plain radiographs and computed tomography but the reliability of these methods has not been assessed. Methods. The Magnetic Resonance Imaging (MRI) images of 180 patients classified by age and gender were evaluated and the most caudal accessible intervertebral disc space was determined from an approach angle beginning at the suprasternal notch. Plain cervical radiographs were also reviewed when available. In patients with multiple imaging studies, the reliability of the measurements was compared. Rate of accessibility was compared across different heights, BMIs, and ages. Results. A novel algorithm that utilized both the scout and mid-sagittal T2 MRIs was able to determine the most caudal cervicothoracic level accessible for anterior access in 93.3% of patients with a reliability of 96.8%. Conversely, plain radiograph evaluation led to low reliability (66.7%) and low agreement with MRI (60%) with an average error of one spinal level. In this patient sample, the T1 to T2 disc space was accessible in 82.7% of patients. Age and BMI were independent variables associated with accessibility (p < 0.01) while height was determined not to be significant (p = 0.09). Conclusion. Data in this study suggest an MRI-based algorithm with a combination of scout and sagittal T2 images offers a reliable and consistent assessment of accessibility to upper thoracic levels through an anterior approach. Age and body mass index are major determinants of accessibility. Level of Evidence: 3