Wireless Measurements Using Electrical Impedance Spectroscopy to Monitor Fracture Healing.

There is an unmet need for improved, clinically relevant methods to longitudinally quantify bone healing during fracture care. Here we develop a smart bone plate to wirelessly monitor healing utilizing electrical impedance spectroscopy (EIS) to provide real-time data on tissue composition within the fracture callus. To validate our technology, we created a 1-mm rabbit tibial defect and fixed the bone with a standard veterinary plate modified with a custom-designed housing that included two impedance sensors capable of wireless transmission. Impedance magnitude and phase measurements were transmitted every 48 h for up to 10 weeks. Bone healing was assessed by X-ray, µCT, and histology. Our results indicated the sensors successfully incorporated into the fracture callus and did not impede repair. Electrical impedance, resistance, and reactance increased steadily from weeks 3 to 7-corresponding to the transition from hematoma to cartilage to bone within the fracture gap-then plateaued as the bone began to consolidate. These three electrical readings significantly correlated with traditional measurements of bone healing and successfully distinguished between union and not-healed fractures, with the strongest relationship found with impedance magnitude. These results suggest that our EIS smart bone plate can provide continuous and highly sensitive quantitative tissue measurements throughout the course of fracture healing to better guide personalized clinical care.

Smart bone plates can monitor fracture healing.

There are currently no standardized methods for assessing fracture healing, with physicians relying on X-rays which are only useful at later stages of repair. Using in vivo mouse fracture models, we present the first evidence that microscale instrumented implants provide a route for post-operative fracture monitoring, utilizing electrical impedance spectroscopy (EIS) to track the healing tissue with high sensitivity. In this study, we fixed mouse long bone fractures with external fixators and bone plates. EIS measurements taken across two microelectrodes within the fracture gap were able to track longitudinal differences between individual mice with good versus poor healing. We additionally present an equivalent circuit model that combines the EIS data to classify fracture repair states. Lastly, we show that EIS measurements strongly correlated with standard quantitative µCT values and that these correlations validate clinically-relevant operating frequencies for implementation of this technique. These results demonstrate that EIS can be integrated into current fracture management strategies such as bone plating, providing physicians with quantitative information about the state of fracture repair to guide clinical decision-making for patients.

FGF and TGFß signaling link form and function during jaw development and evolution.

How does form arise during development and change during evolution? How does form relate to function, and what enables embryonic structures to presage their later use in adults? To address these questions, we leverage the distinct functional morphology of the jaw in duck, chick, and quail. In connection with their specialized mode of feeding, duck develop a secondary cartilage at the tendon insertion of their jaw adductor muscle on the mandible. An equivalent cartilage is absent in chick and quail. We hypothesize that species-specific jaw architecture and mechanical forces promote secondary cartilage in duck through the differential regulation of FGF and TGFß signaling. First, we perform transplants between chick and duck embryos and demonstrate that the ability of neural crest mesenchyme (NCM) to direct the species-specific insertion of muscle and the formation of secondary cartilage depends upon the amount and spatial distribution of NCM-derived connective tissues. Second, we quantify motility and build finite element models of the jaw complex in duck and quail, which reveals a link between species-specific jaw architecture and the predicted mechanical force environment. Third, we investigate the extent to which mechanical load mediates FGF and TGFß signaling in the duck jaw adductor insertion, and discover that both pathways are mechano-responsive and required for secondary cartilage formation. Additionally, we find that FGF and TGFß signaling can also induce secondary cartilage in the absence of mechanical force or in the adductor insertion of quail embryos. Thus, our results provide novel insights on molecular, cellular, and biomechanical mechanisms that couple musculoskeletal form and function during development and evolution.

Using impedance to track fracture healing rates in mice in vivo: A pilot study.

Fracture injuries are highly prevalent worldwide, with treatment of problematic fractures causing a significant burden on the U.S. healthcare system. Physicians typically monitor fracture healing by conducting physical examinations and taking radiographic images. However, nonunions currently take over 6 months to be diagnosed because these techniques are not sensitive enough to adequately assess fracture union. In this study, we display the utility of impedance spectroscopy to track different healing rates in a pilot study of an in vivo mouse tibia fracture model. We have developed small (56 µm) sensors and implanted them in an externally-stabilized fracture for twice-weekly measurement. We found that impedance magnitude increases steadily over time in healing mice but stalls in non-healing mice, and phase angle displays frequency-dependent behavior that also reflects the extent of healing at the fracture site. Our results demonstrate that impedance can track differences in healing rates early on, highlighting the potential of this technique as a method for early detection of fracture nonunion.

New opportunities for fracture healing detection: Impedance spectroscopy measurements correlate to tissue composition in fractures.

Accurate evaluation of fracture healing is important for clinical decisions on when to begin weight-bearing and when early intervention is necessary in cases of fracture nonunion. While the stages of healing involving hematoma, cartilage, trabecular bone, and cortical bone have been well characterized histologically, physicians typically track fracture healing by using subjective physical examinations and radiographic techniques that are only able to detect mineralized stages of bone healing. This exposes the need for a quantitative, reliable technique to monitor fracture healing, and particularly to track healing progression during the early stages of repair. The goal of this study was to validate the use of impedance spectroscopy to monitor fracture healing and perform comprehensive evaluation comparing measurements with histological evidence. Here, we show that impedance spectroscopy not only can distinguish between cadaver tissues involved throughout fracture repair, but also correlates to fracture callus composition over the middle stages of healing in wild-type C57BL/6 mice. Specifically, impedance magnitude has a positive relationship with % trabecular bone and a negative relationship with % cartilage, and the opposite relationships are found when comparing phase angle to these same volume fractions of tissues. With this information, we can quantitatively evaluate how far a fracture has progressed through the healing stages. Our results demonstrate the feasibility of impedance spectroscopy for detection of fracture callus composition and reveals its potential as a method for early detection of bone healing and fracture nonunion. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2620-2629, 2017.

Biomechanical comparison of long, short, and extended-short nail construct for femoral intertrochanteric fractures.

OBJECTIVES: Short and long cephalomedullary (CM) nails are commonly used construct for fixation of intertrochanteric (IT) fractures. Each of these constructs has its advantages and its shortcomings. The extended-short (ES) CM nail offers a hybrid between long and short nail design that aims to combine their respective benefits. The goals of this study were to (1) biomechanically evaluate and compare construct stiffness for the long, short and ES constructs in the fixation of IT fractures, and to (2) investigate the nature of periprosthetic fractures of constructs implanted with these various designs. METHODS: Eighteen synthetic femora were used to evaluate three types of fracture fixation constructs. Axial compression, bending, and torsional stiffness were reported for both stable and comminuted IT fracture models. All comminuted fracture constructs were loaded to failure in axial compression to measure failure loads and evaluate periprosthetic fracture patterns. RESULTS: Stiffness were similar among constructs with few exceptions. Axial stiffness was significantly higher for the short nail compared to the long nail for the comminuted model (p= 0.020). ES nail constructs exhibited a significantly higher failure load than short nail constructs (p = 0.039). Periprosthetic fractures occurred around the distal interlocking screw in all constructs. CONCLUSIONS: Nail length and position of interlocking screw did not alter the biomechanical properties of the fixation construct in the presented IT fracture model. Periprosthetic fractures generated in this study had similar patterns to those seen clinically. This study also suggests that if a periprosthetic fracture is to occur, there is an increased probability of it happening around the site of the interlocking screw, regardless of nail design.

Impedance spectroscopy to monitor fracture healing.

An estimated 7.9 million fracture injuries occur each year in the United States, of which a substantial fraction result in delayed or non-union. Current methods of monitoring fracture healing include taking x-rays and making clinical observations. However, x-ray confirmation of bone healing typically lags behind biologic healing, and physician assessment of healing is fraught with subjectivity. No standardized methods exist to assess the extent of healing that has taken place in a fracture. Without such knowledge, interventions to aid healing and prevent fracture non-union are often delayed, leading to increased morbidity and suffering to patients. We are developing an objective measurement tool that utilizes electrical impedance spectroscopy to distinguish between the various types of tissue present during the different stages of fracture healing. Preliminary measurements of cadaveric tissues reveal adequate spread in impedance measurements and differences in frequency response among different tissue types. Electrodes implanted in a simulated fracture created in an ex vivo cadaver model yield promising results for our system's ability to differentiate between the stages of fracture healing.

Primary and secondary restraints of human and ovine knees for simulated in vivo gait kinematics.

Knee soft tissue structures are frequently injured, leading to the development of osteoarthritis even with treatment. Understanding how these structures contribute to knee function during activities of daily living (ADLs) is crucial in creating more effective treatments. This study was designed to determine the role of different knee structures during a simulated ADL in both human knees and ovine stifle joints. A six degree-of-freedom robot was used to reproduce each species' in vivo gait while measuring three-dimensional joint forces and torques. Using a semi-randomized selective cutting method, we determined the primary and secondary structures contributing to the forces and torques along and about each anatomical axis. In both species, the bony interaction, ACL, and medial meniscus provided most of the force contributions during stance, whereas the ovine MCL, human bone, and ACLs of both species were the key contributors during swing. This study contributes to our overarching goal of establishing functional tissue engineering parameters for knee structures by further validating biomechanical similarities between the ovine model and the human to provide a platform for measuring biomechanics during an in vivo ADL. These parameters will be used to develop more effective treatments for knee injuries to reduce or eliminate the incidence of osteoarthritis.

Effect of perturbing a simulated motion on knee and anterior cruciate ligament kinetics.

Current surgical treatments for common knee injuries do not restore the normal biomechanics. Among other factors, the abnormal biomechanics increases the susceptibility to the early onset of osteoarthritis. In pursuit of improving long term outcome, investigators must understand normal knee kinematics and corresponding joint and anterior cruciate ligament (ACL) kinetics during the activities of daily living. Our long term research goal is to measure in vivo joint motions for the ovine stifle model and later simulate these motions with a 6 degree of freedom (DOF) robot to measure the corresponding 3D kinetics of the knee and ACL-only joint. Unfortunately, the motion measurement and motion simulation technologies used for our project have associated errors. The objective of this study was to determine how motion measurement and motion recreation error affect knee and ACL-only joint kinetics by perturbing a simulated in vivo motion in each DOF and measuring the corresponding intact knee and ACL-only joint forces and moments. The normal starting position for the motion was perturbed in each degree of freedom by four levels (-0.50, -0.25, 0.25, and 0.50 mm or degrees). Only translational perturbations significantly affected the intact knee and ACL-only joint kinetics. The compression-distraction perturbation had the largest effect on intact knee forces and the anterior-posterior perturbation had the largest effect on the ACL forces. Small translational perturbations can significantly alter intact knee and ACL-only joint forces. Thus, translational motion measurement errors must be reduced to provide a more accurate representation of the intact knee and ACL kinetics. To account for the remaining motion measurement and recreation errors, an envelope of forces and moments should be reported. These force and moment ranges will provide valuable functional tissue engineering parameters (FTEPs) that can be used to design more effective ACL treatments.

Applying simulated in vivo motions to measure human knee and ACL kinetics.

Patients frequently experience anterior cruciate ligament (ACL) injuries but current ACL reconstruction strategies do not restore the native biomechanics of the knee, which can contribute to the early onset of osteoarthritis in the long term. To design more effective treatments, investigators must first understand normal in vivo knee function for multiple activities of daily living (ADLs). While the 3D kinematics of the human knee have been measured for various ADLs, the 3D kinetics cannot be directly measured in vivo. Alternatively, the 3D kinetics of the knee and its structures can be measured in an animal model by simulating and applying subject-specific in vivo joint motions to a joint using robotics. However, a suitable biomechanical surrogate should first be established. This study was designed to apply a simulated human in vivo motion to human knees to measure the kinetics of the human knee and ACL. In pursuit of establishing a viable biomechanical surrogate, a simulated in vivo ovine motion was also applied to human knees to compare the loads produced by the human and ovine motions. The motions from the two species produced similar kinetics in the human knee and ACL. The only significant difference was the intact knee compression force produced by the two input motions.

Effect of surgery to implant motion and force sensors on vertical ground reaction forces in the ovine model.

Activities of daily living (ADLs) generate complex, multidirectional forces in the anterior cruciate ligament (ACL). While calibration problems preclude direct measurement in patients, ACL forces can conceivably be measured in animals after technical challenges are overcome. For example, motion and force sensors can be implanted in the animal but investigators must determine the extent to which these sensors and surgery affect normal gait. Our objectives in this study were to determine (1) if surgically implanting knee motion sensors and an ACL force sensor significantly alter normal ovine gait and (2) how increasing gait speed and grade on a treadmill affect ovine gait before and after surgery. Ten skeletally mature, female sheep were used to test four hypotheses: (1) surgical implantation of sensors would significantly decrease average and peak vertical ground reaction forces (VGRFs) in the operated limb, (2) surgical implantation would significantly decrease single limb stance duration for the operated limb, (3) increasing treadmill speed would increase VGRFs pre- and post operatively, and (4) increasing treadmill grade would increase the hind limb VGRFs pre- and post operatively. An instrumented treadmill with two force plates was used to record fore and hind limb VGRFs during four combinations of two speeds (1.0 m/s and 1.3 m/s) and two grades (0 deg and 6 deg). Sensor implantation decreased average and peak VGRFs less than 10% and 20%, respectively, across all combinations of speed and grade. Sensor implantation significantly decreased the single limb stance duration in the operated hind limb during inclined walking at 1.3 m/s but had no effect on single limb stance duration in the operated limb during other activities. Increasing treadmill speed increased hind limb peak (but not average) VGRFs before surgery and peak VGRF only in the unoperated hind limb during level walking after surgery. Increasing treadmill grade (at 1 m/s) significantly increased hind limb average and peak VGRFs before surgery but increasing treadmill grade post op did not significantly affect any response measure. Since VGRF values exceeded 80% of presurgery levels, we conclude that animal gait post op is near normal. Thus, we can assume normal gait when conducting experiments following sensor implantation. Ultimately, we seek to measure ACL forces for ADLs to provide design criteria and evaluation benchmarks for traditional and tissue engineered ACL repairs and reconstructions.

Eversion technique increases the risk for post-carotid endarterectomy hypertension.

OBJECTIVE: The incidence of postoperative hypertension (HTN) after eversion carotid endarterectomy (e-CEA) was compared with that after standard carotid endarterectomy (s-CEA). METHODS: In a retrospective analysis from January 1998 to January 2000, 217 patients underwent 219 CEAs for symptomatic (68) or asymptomatic (151) high-grade (>80%) carotid artery stenosis by either standard (137) or eversion (82) techniques. The eversion technique involves an oblique transection of the internal carotid artery at the carotid bulb and a subsequent endarterectomy by everting the internal carotid artery over the atheromatous plaque. All procedures were done under general anesthesia, and somatosensory-evoked potentials were used for cerebral monitoring. Patients with s-CEA were compared with those with e-CEA for postoperative hemodynamic instability, carotid sinus nerve block, requirement for intravenous vasodilators or vasopressors, stroke, and death. RESULTS: Patients who underwent e-CEA had a significantly (P <.005) increased postoperative blood pressure and required more frequent intravenous antihypertensive medication (24%), compared with patients having an s-CEA (6%). Furthermore, postoperative vasopressors were required after 10% of s-CEAs, but after none of the e-CEAs. No statistically significant difference was noted in the morbidity or mortality of patients after s-CEA and e-CEA. CONCLUSION: e-CEA is a substantial risk factor for HTN in the immediate postoperative period, when compared with the s-CEA. This difference would be even more remarkable in the absence of antihypertensive medications in the e-CEA group and vasopressors in the s-CEA group. Therefore, particular attention should be focused on diagnosing and controlling postoperative HTN in patients after e-CEA.

The validity of the general ability measure for adults: comparison with WAIS-R IQ scores in a sample of college students with academic difficulties.

The present study investigated the validity of the General Ability Measure for Adults (GAMA) by comparing it to the WAIS-R using a sample of 80 college students reporting learning difficulties. Results indicated that the mean GAMA IQ score did not deviate significantly from the mean WAIS-R IQ scores. The GAMA Full Scale IQ correlated significantly with the WAIS-R PIQ, VIQ, and FSIQ scores. However, the obtained correlation coefficient for the GAMA and WAIS-R PIQ significantly differed from the observed correlation coefficient between the GAMA and WAIS-R VIQ, suggesting that the GAMA was more clearly associated with perceptual skills than verbal abilities. When the correlation coefficients between the GAMA and WAIS-R scores were corrected for the effects of range restriction, the correlation coefficients increased, yet demonstrated the same pattern (e.g., GAMA/PIQ,.69; GAMA/VIQ,.36; GAMA/FSIQ,.60). The GAMA s accuracy in predicting individual student performance on the WAIS-R FSIQ also was examined.

Management of coexisting coronary artery and asymptomatic carotid artery disease: report of a series of patients treated with coronary bypass alone.

BACKGROUND: A retrospective chart review of 94 patients with asymptomatic high-grade carotid stenosis undergoing coronary bypass (and valve replacement in some cases) was performed to determine whether significant carotid lesions can be safely ignored in patients undergoing cardiac surgical procedures. These operations were performed during a 2-year period. PATIENTS AND METHODS: There were 55 men and 39 women, with an age range of 37-89 years. Seventy-one patients had unilateral high-grade carotid stenosis, 17 patients had bilateral high-grade lesions, and six patients had unilateral high-grade stenosis and contralateral occlusion. Associated medical problems were recorded and short-term follow-up was obtained. RESULTS: There was one perioperative stroke and no deaths in this group of patients. CONCLUSIONS: Although these data indicate that high-grade carotid stenoses may be safely ignored during cardiac surgical procedures, a multicentre prospective randomized trial is needed to determine the appropriate treatment of the patient with coexisting carotid and coronary artery disease.

Plasma factor VII and thrombin-antithrombin III levels indicate increased tissue factor activity in sickle cell patients.

Although the mechanisms involved in the persistent clinical complications of sickle cell disease have not yet been fully delineated, previous studies suggest that sickle cell (HbSS) patients have a disposition to generate more thrombin and plasma in vivo than normal subjects. The reasons for the impaired regulation of haemostasis in HbSS patients is poorly understood. We report studies evaluating the extent to which in vivo coagulation and fibrinolysis are altered in HbSS patients in steady state. The concentrations of total factor VII (F(VII)t), factor VII zymogen (F(VII)z), thrombin-antithrombin III (TAT), fibrinopeptide A(FPA), and fibrin D-dimer in plasmas of 50 normal controls (HbAA) and 45 HbSS steady state patients, were measured using sensitive and specific enzyme-linked immunoassays. The average plasma concentration of F(VII)t, in sickle cell plasma was significantly lower than that of the control subjects (0.70 +/- 0.19 U/ml versus 1.16 +/- 0.41 U/ml), whereas F(VII)z in the patients and controls were 0.47 +/- 0.15 U/ml and 1.15 +/- 0.33 U/ml respectively, P < 0.001. Both measures of factor VII suggest a higher factor VII turnover in sickle cell disease. The mean concentration of TAT in the plasma of HbSS patients were significantly higher than those of HbAA controls (371 +/- 44 pM versus 42 +/- 2 pM) (P < 0.001), a difference that is strongly indicative of higher rates of in vivo thrombin generation by HbSS patients. Plasmas of HbSS patients had significantly higher concentrations of FPA compared to those of the control subjects (12.85 +/- 1.96 ng/ml versus 4.22 +/- 0.37 ng/ml) (P < 0.001). The D-dimer levels were also higher in the HbSS than control plasmas (1029.6 +/- 58.6 ng/ml versus 224.3 +/- 27.6 g/ml) (P < 0.001), with the patients' values being indicative of enhanced fibrinolysis. These results strongly suggest accelerated in vivo coagulation and fibrinolysis in HbSS patients even during steady state. They are consistent with the hypothesis that haemostasis is less tightly regulated in the HbSS patients than in HbAA controls. The altered regulation of haemostasis may contribute to the initiation of vaso-occlusive processes associated with sickle cell painful episodes.