Alan W. Eberhardt

Activation of the hypoxia-inducible factor-1alpha pathway accelerates bone regeneration.

The hypoxia-inducible factor-1α (HIF-1α) pathway is the central regulator of adaptive responses to low oxygen availability and is required for normal skeletal development. Here, we demonstrate that the HIF-1α pathway is activated during bone repair and can be manipulated genetically and pharmacologically to improve skeletal healing. Mice lacking pVHL in osteoblasts with constitutive HIF-1α activation in osteoblasts had markedly increased vascularity and produced more bone in response to distraction osteogenesis, whereas mice lacking HIF-1α in osteoblasts had impaired angiogenesis and bone healing. The increased vascularity and bone regeneration in the pVHL mutants were VEGF dependent and eliminated by concomitant administration of VEGF receptor antibodies. Small-molecule inhibitors of HIF prolyl hydroxylation stabilized HIF/VEGF production and increased angiogenesis in vitro. One of these molecules (DFO) administered in vivo into the distraction gap increased angiogenesis and markedly improved bone regeneration. These results identify the HIF-1α pathway as a critical mediator of neoangiogenesis required for skeletal regeneration and suggest the application of HIF activators as therapies to improve bone healing.

Quasi-linear viscoelastic behavior of the human periodontal ligament.

Previous studies have not produced a comprehensive mathematical description of the nonlinear viscoelastic stress-strain behavior of the periodontal ligament (PDL). In the present study, the quasi-linear viscoelastic (QLV) model was applied to mechanical tests of the human PDL. Transverse sections of cadaveric premolars were subjected to relaxation tests and loading to failure perpendicular to the plane of section. Distinct and repeatable toe and linear regions of stress-strain behavior were observed. The amount of strain associated with the toe region differed as a function of anatomical location along the tooth root. Stress relaxation behavior was comparable for different anatomical locations. Model predicted peak tissue stresses for cyclic loading were within 11% of experimental values, demonstrating that the QLV approach provided an improved, accurate quantification of PDL mechanical response. The success of the QLV approach supports its usefulness in future efforts of experimental characterization of PDL mechanical behavior.

A nonlinear finite element analysis of the periodontal ligament under orthodontic tooth loading

The stressed state of the periodontal ligament (PDL) is understood to play a critical role in the tooth movement initiated by orthodontic treatment. Finite element simulations have been used to describe PDL stresses for orthodontic loading; however, these models have predominantly assumed linear mechanical properties for the PDL. The present study sought to determine the importance of using nonlinear mechanical properties and nonuniform geometric data in computer predictions of periodontal ligament stresses and tooth movements. A 2-dimensional plane-strain finite element model of a mandibular premolar was constructed based on anatomic data of transverse sections of tooth, PDL, and bone from a 24-year-old cadaveric man. A second model was constructed of the same tooth but with a PDL of uniform thickness. Each of these was prescribed linear or nonlinear elastic mechanical properties, as obtained in our own experiments. Predictions of the maximum and minimum principal stresses and von Mises stresses in the PDL were determined for extrusive and tipping forces. The results indicated that biofidelic finite element models predicted substantially different stresses in the PDL for extrusive loading than did the uniform thickness model, suggesting that incorporation of the hourglass shape of the PDL is warranted. In addition, incorporation of nonlinear mechanical properties for the PDL resulted in dramatic increases in the stresses at the apex and cervical margin as compared with the linear models.

Bone mineral density correlates with fracture load in experimental side impacts of the pelvis

Pelvic fractures resulting from automotive side impacts are associated with high mortality and morbidity, as well as substantial economic costs. Previous experimental studies have produced varying results regarding the tolerance of the pelvis to lateral force and compression. While bone mineral density (BMD) has been shown to correlate with fracture loads in the proximal femur, no such correlation has been established for the pelvis. Presently, we studied the relationships between total hip BMD and impact response parameters in lateral impacts of twelve isolated human pelves. The results indicated that total hip BMD significantly correlated with fracture force, Fmax, and maximum ring compression, Cmax, of the fractured pelves. These findings are evidence that BMD may be useful in assessing the risk of pelvic fracture in automotive side impacts. Poor correlation was observed between total hip BMD and maximum viscous response, (VC)max, energy at fracture, Epeak, and time to fracture, tpeak. Mean Fmax and calculated tolerances for Cmax and (VC)max were lower than those established in previous studies using full cadavers, likely a result of our removal of soft tissues from the pelves prior to impact.

Activation of the hypoxia-inducible factor-1α pathway accelerates bone regeneration

The hypoxia-inducible factor-1α (HIF-1α) pathway is the central regulator of adaptive responses to low oxygen availability and is required for normal skeletal development. Here, we demonstrate that the HIF-1α pathway is activated during bone repair and can be manipulated genetically and pharmacologically to improve skeletal healing. Mice lacking pVHL in osteoblasts with constitutive HIF-1α activation in osteoblasts had markedly increased vascularity and produced more bone in response to distraction osteogenesis, whereas mice lacking HIF-1α in osteoblasts had impaired angiogenesis and bone healing. The increased vascularity and bone regeneration in the pVHL mutants were VEGF dependent and eliminated by concomitant administration of VEGF receptor antibodies. Small-molecule inhibitors of HIF prolyl hydroxylation stabilized HIF/VEGF production and increased angiogenesis in vitro. One of these molecules (DFO) administered in vivo into the distraction gap increased angiogenesis and markedly improved bone regeneration. These results identify the HIF-1α pathway as a critical mediator of neoangiogenesis required for skeletal regeneration and suggest the application of HIF activators as therapies to improve bone healing.

Early Failure of a Cross-Linked Polyethylene Acetabular Liner: A Case Report

The use of highly cross-linked ultra-high molecular weight polyethylene in total hip arthroplasty has become a popular alternative to the use of conventional polyethylene. Evaluations with use of hip simulator tests1-4 and clinical evaluations of total hip replacements5-10 have independently shown that polyethylene materials processed with gamma irradiation followed by melting or annealing have extremely low wear rates. However, it also has been demonstrated that such cross-linking processes may reduce the fracture toughness and resistance to fatigue crack propagation of polyethylene11-16. Bradford et al.14 found that retrieved cross-linked polyethylene acetabular liners exhibited surface cracking that had not been predicted by in vitro hip simulator studies. Tower et al.17 observed fatigue failure at the superior aspect of the rim of four retrieved highly cross-linked acetabular bearings. They concluded that the factors contributing to these failures included thin polyethylene at the cup rim, a relatively vertical cup alignment, and compromised material properties of the cross-linked polyethylene in comparison with conventional polyethylene. In the current case report, we describe the failure of a highly cross-linked polyethylene acetabular liner less than three years after implantation. We believe that the mechanisms of failure were fracture of the cross-linked polyethylene where it was thin along the locking groove and abnormal loading of the cup because of improper seating of the liner in the shell at the time of the original procedure. This study was conducted with institutional review board approval and in compliance with HIPAA (Health Insurance Portability and Accountability Act) requirements at our institution. A seventy-four-year-old woman underwent a primary right total hip replacement through a posterior minimally invasive approach. The femoral component was a VerSys Advocate cemented stem (Zimmer, Warsaw, Indiana) with a satin surface finish, a 34-mm neck length, and a …

Three-dimensional finite element models of the human pubic symphysis with viscohyperelastic soft tissues.

Three-dimensional finite element (FE) models of human pubic symphyses were constructed from computed tomography image data of one male and one female cadaver pelvis. The pubic bones, interpubic fibrocartilaginous disc and four pubic ligaments were segmented semi-automatically and meshed with hexahedral elements using automatic mesh generation schemes. A two-term viscoelastic Prony series, determined by curve fitting results of compressive creep experiments, was used to model the rate-dependent effects of the interpubic disc and the pubic ligaments. Three-parameter Mooney-Rivlin material coefficients were calculated for the discs using a heuristic FE approach based on average experimental joint compression data. Similarly, a transversely isotropic hyperelastic material model was applied to the ligaments to capture average tensile responses. Linear elastic isotropic properties were assigned to bone. The applicability of the resulting models was tested in bending simulations in four directions and in tensile tests of varying load rates. The model-predicted results correlated reasonably with the joint bending stiffnesses and rate-dependent tensile responses measured in experiments, supporting the validity of the estimated material coefficients and overall modeling approach. This study represents an important and necessary step in the eventual development of biofidelic pelvis models to investigate symphysis response under high-energy impact conditions, such as motor vehicle collisions.

Acetabular Fracture Patterns: Associations with Motor Vehicle Crash Information

BACKGROUND Motor vehicle crashes are the most common cause of acetabular fractures, which have been associated with significant morbidity and mortality. METHODS To date, medical and collision information has been collected on 83 acetabular fracture patients treated at the University of Alabama at Birminghams Level I trauma center. The fractures were grouped according to the Judet-Letournel classification scheme and investigated for correlation with age, sex, vehicle type, impact direction, and seat-belt use. RESULTS The database included 41 women and 42 men with a combined average age of 32.8 years. Femoral shaft axis loading fractures correlated significantly with male sex, trucks, and frontal impacts. Greater trochanter loading fractures occurred statistically more frequently in side impacts. Women received a significant higher percentage of off-axis loading fractures, which were associated more in angled frontal impacts. CONCLUSION Acetabular fracture type strongly correlated with impact direction, supporting the fracture mechanisms proposed by Judet and Letournel.

Effects of trochanteric soft tissues and bone density on fracture of the female pelvis in experimental side impacts

Pelvic fractures continue to be a source of morbidity and mortality for occupants in motor vehicle side impacts, especially among women. Previous studies have produced fracture tolerances for the female pelvis, yet the roles of soft tissues and bone quality remain unclear. Presently, we studied the influence of trochanteric soft tissue thickness (T) and total hip bone mineral density (BMD) on pelvic fracture of 10 female human pelves subject to lateral impact centered over the greater trochanter. Multiple impacts of increasing severity were performed and impact force, energy, impulse, compression, and viscous criteria were quantified. BMD and T were found to be additive predictors of the fracture force. For a given BMD, the force to fracture was significantly higher than that found previously using isolated pelvic bones. Impulse was found to positively correlate with T; however, maximum compression, viscous criterion, and energy to fracture were independent of BMD and T. The force tolerance at 25% probability of fracture found presently (3.16 kN) is substantially below previously reported values. The results suggest that the trochanteric soft tissue thickness and total hip BMD have a significant bearing on fracture outcome for the female pelvis in automotive side impact.

Elastic and Viscoelastic Properties of the Human Pubic Symphysis Joint: Effects of Lateral Impact Loading

The human pelvis is susceptible to severe injury in vehicle side impacts owing to its close proximity to the intruding door and unnatural loading through the greater trochanter. Whereas fractures of the pelvic bones are diagnosed with routine radiographs (x-rays) and computerized tomography (CT scans), non-displaced damage to the soft tissues of pubic symphysis joints may go undetected. If present, trauma-induced joint laxity may cause pelvic instability, which has been associated with pelvic pain in non-traumatic cases. In this study, mechanical properties of cadaveric pubic symphysis joints from twelve normal and eight laterally impacted pelves were compared. Axial stiffness and creep responses of these isolated symphyses were measured in tension and compression (perpendicular to the joint). Bending stiffness was determined in four primary directions followed by a tension-to-failure test. Loading rate and direction correlated significantly (p<0.05) with stiffness and tensile strength of the unimpacted joints, more so than donor age or gender. The impacted joints had significantly lower stiffness in tension (p <0.04), compression (p<0.003), and posterior bending (p<0.03), and more creep under a compressive step load (p<0.008) than the unimpacted specimens. Tensile strength was reduced following impact, however, not significantly. We concluded that the symphysis joints from the impacted pelves had greater laxity, which may correlate with post-traumatic pelvic pain in some motor vehicle crash occupants.