Evidence of Autoimmune Involvement in the Pathogenesis of Charcot Neuroarthropathy: A Novel Hypothesis with Preliminary Data.

Charcot neuroarthropathy is a devastating condition that places patients at risk for poor outcomes. Although the condition was first described in 1703, knowledge of the causative agent(s) has yet to be fully understood. Recent advances in genetic research have helped to identify potential mechanisms and pathways for the enigmatic destruction and deformities that are often associated with the condition; however, alternative pathways have been proposed. For the purpose of this discussion, we will discuss the human leukocyte antigen, which is one of the most researched contributors to autoimmune pathology and, more recently, has been linked to diabetic complications.

Template models for simulation of surface manipulation of musculoskeletal extremities.

Capturing the surface mechanics of musculoskeletal extremities would enhance the realism of life-like mechanics imposed on the limbs within surgical simulations haptics. Other fields that rely on surface manipulation, such as garment or prosthetic design, would also benefit from characterization of tissue surface mechanics. Eight homogeneous tissue models were developed for the upper and lower legs and arms of two donors. Ultrasound indentation data was used to drive an inverse finite element analysis for individualized determination of region-specific material coefficients for the lumped tissue. A novel calibration strategy was implemented by using a ratio based adjustment of tissue properties from linear regression of model predicted and experimental responses. This strategy reduced requirement of simulations to an average of under four iterations. These free and open-source specimen-specific models can serve as templates for simulations focused on mechanical manipulations of limb surfaces.

Reference data on in vitro anatomy and indentation response of tissue layers of musculoskeletal extremities.

The skin, fat, and muscle of the musculoskeletal system provide essential support and protection to the human body. The interaction between individual layers and their composite structure dictate the body's response during mechanical loading of extremity surfaces. Quantifying such interactions may improve surgical outcomes by enhancing surgical simulations with lifelike tissue characteristics. Recently, a comprehensive tissue thickness and anthropometric database of in vivo extremities was acquired using a load sensing instrumented ultrasound to enhance the fidelity of advancing surgical simulations. However detailed anatomy of tissue layers of musculoskeletal extremities was not captured. This study aims to supplement that database with an enhanced dataset of in vitro specimens that includes ultrasound imaging supported by motion tracking of the ultrasound probe and two additional full field imaging modalities (magnetic resonance and computed tomography). The additional imaging datasets can be used in conjunction with the ultrasound/force data for more comprehensive modeling of soft tissue mechanics. Researchers can also use the image modalities in isolation if anatomy of legs and arms is needed.

Regional variations of in vivo surface stiffness of soft tissue layers of musculoskeletal extremities.

Surface stiffness of bulk soft tissue in musculoskeletal extremities is important to consider in the design of prosthetics, exoskeletons, and protective gear. This knowledge is also foundational for surgical simulation and clinical interventions leveraging manipulation of the musculoskeletal surfaces. Injuries to musculoskeletal extremities are common and surgical and preventive interventions require interactions between various objects such as surgical tools and support surfaces with tissue boundaries. While a handful of investigations examined the variations in indentation mechanics due to pathology or injury specific sites, a comprehensive analysis across the surfaces of musculoskeletal extremities has not been completed. In this study we examine variations of surface stiffness across 8 sites of the upper and lower arms and legs for 95 subjects using an instrumented ultrasound device. Differences in surface stiffness were observed between gender, activity level, and indentation location groups. The lower arm posterior location had the highest average stiffness (3.89 × 10-3 MPa/mm), while the lowest stiffness was observed at the upper leg posterior location (0.98 × 10-3 MPa/mm). The differences between indentation sites were larger in magnitude when compared to differences due to demographics (gender and activity level). However the large ranges of the 95% confidence intervals suggest that an aggregated metric based on population or sub-group may not capture individual variations. This study implicates the motivation to explore tissue composition variations within the indentation sites as well as the potential importance to include variations in surface stiffness during surgical simulations.

Instrumentation of off-the-shelf ultrasound system for measurement of probe forces during freehand imaging.

Ultrasound is a popular and affordable imaging modality, but the nature of freehand ultrasound operation leads to unknown applied loads at non-quantifiable angles. The purpose of this paper was to demonstrate an instrumentation strategy for an ultrasound system to measure probe forces and orientation during freehand imaging to characterize the interaction between the probe and soft-tissue as well as enhance repeatability. The instrumentation included a 6-axis load cell, an inertial measurement unit, and an optional sensor for camera-based motion capture. A known method for compensation of the ultrasound probe weight was implemented, and a novel method for temporal synchronization was developed. While load and optical sensing was previously achieved, this paper presents a strategy for potential instrumentation on a variety of ultrasound machines. A key feature was the temporal synchronization, utilizing the electrocardiogram (EKG) feature built-in to the ultrasound. The system was used to perform anatomical imaging of tissue layers of musculoskeletal extremities and imaging during indentation on an in vivo subject and an in vitro specimen. The outcomes of the instrumentation strategy were demonstrated during minimal force and indentation imaging. In short, the system presented robust instrumentation of an existing ultrasound system to fully characterize the probe force, orientation, and optionally its movement during imaging while efficiently synchronizing all data. Researchers may use the instrumentation strategy on any EKG capable ultrasound systems if mechanical characterization of soft tissue or minimization of forces and deformations of tissue during anatomical imaging are desired.

Open-label Extension Phase of a Chronic Diabetic Foot Ulcer Multicenter, Controlled, Randomized Clinical Trial Using Cryopreserved Placental Membrane.

OBJECTIVE: The results of the single-arm, open-label extension phase of the Grafix (cryopreserved placental membrane; CPM; Osiris Therapeutics, Inc, Columbia, MD) multicenter, blinded, randomized, controlled clinical trial for chronic diabetic foot ulcers (DFUs) is reported. MATERIALS AND METHODS: Twenty-six patients in the standard wound care (SWC) arm whose DFUs did not close in the blinded phase chose to receive weekly applications of the CPM in an open-label extension phase. RESULTS: In the extension phase, 17 (65.4%) patients closed their wounds in a median of 34 days and 3 visits. There were fewer total adverse events (AEs) (24 CPM vs. 52 SWC) and index wound-related infections (5 CPM vs. 12 SWC) during the CPM application compared with the number of AEs for the same patients during the SWC treatment in the blinded phase of the trial. CONCLUSIONS: These results corroborate the benefits of this CPM combined with SWC over SWC alone for chronic DFUs previously reported for the blinded randomized phase of the trial, which directly relate to lower health care costs.

Reference data on thickness and mechanics of tissue layers and anthropometry of musculoskeletal extremities.

Musculoskeletal extremities exhibit a multi-layer tissue structure that is composed of skin, fat, and muscle. Body composition and anthropometric measurements have been used to assess health status and build anatomically accurate biomechanical models of the limbs. However, comprehensive datasets inclusive of regional tissue anatomy and response under mechanical manipulation are missing. The goal of this study was to acquire and disseminate anatomical and mechanical data collected on extremities of the general population. An ultrasound system, instrumented with a load transducer, was used for in vivo characterization of skin, fat, and muscle thicknesses in the extremities of 100 subjects at unloaded (minimal force) and loaded (through indentation) states. For each subject, the unloaded and loaded state provided anatomic tissue layer measures and tissue indentation response for 48 and 8 regions, respectively. A publicly available web-based system has been used for data management and dissemination. This comprehensive database will provide the foundation for comparative studies in regional musculoskeletal composition and improve visual and haptic realism for computational models of the limbs.

Evaluating Iatrogenic Complications of the Total-Contact Cast: An 8-Year Retrospective Review at Cleveland Clinic.

BACKGROUND: Total-contact casting is an effective method to treat various pathologic abnormalities in patients with diabetic neuropathy, but its use is frequently associated with iatrogenic complications. METHODS: The largest retrospective review to date of iatrogenic complications of total-contact casts was conducted over an 8-year period at Cleveland Clinic. RESULTS: In the past 8 years, 23% of patients developed complications, and the most common complication was a new heel ulcer formation. Of these complications, 92.1% resolved, 6.4% were lost to follow-up, and 1.4% resulted in a partial foot amputation. Mean cast duration was 10.3 days for patients who developed a total-contact cast iatrogenic complication. The most common indication for the use of a total-contact cast was a neuropathic foot ulceration. CONCLUSIONS: The results of this study support the use of total-contact casting in the insensate patient with diabetes. However, adequate staff training in total-contact cast application is recommended to reduce complications.

Replacement of daily load attenuates but does not prevent changes to the musculoskeletal system during bed rest.

The dose-response effects of exercise in reduced gravity on musculoskeletal health have not been well documented. It is not known whether or not individualized exercise prescriptions can be effective in preventing the substantial loss in bone mineral density and muscle function that have been observed in space flight and in bed rest. In this study, typical daily loads to the lower extremities were quantified in free-living subjects who were then randomly assigned to control or exercise groups. Subjects were confined to 6-degree head-down bed rest for 84 days. The exercise group performed individually prescribed 1 g loaded locomotor exercise to replace their free-living daily load. Eleven subjects (5 exercise, 6 control) completed the protocol. Volumetric bone mineral density results from quantitative computed tomography demonstrated that control subjects lost significant amounts of bone in the intertrochanteric and total hip regions (p < 0.0125), whereas the exercise group showed no significant change from baseline in any region (p > 0.0125). Pre-and post-bed rest muscle volumes were calculated from analysis of magnetic resonance imaging data. The exercise group retained a larger percentage of their total quadriceps and gastrocnemius muscle volume (- 7.2% ± 5.9, - 13.8% ± 6.1, respectively) than their control counterparts (- 23.3% ± 5.9, - 33.0 ± 8.2, respectively; p < 0.01). Both groups significantly lost strength in several measured activities (p < 0.05). The declines in peak torque during repeated exertions of knee flexion and knee extension were significantly less in the exercise group than in the control group (p < 0.05) but work done was not significantly different between groups (p > 0.05). The decline in VO2max was 17% ± 18 in exercising subjects (p < 0.05) and 31% ± 13 in control subjects (p = 0.003; difference between groups was not significant p = 0.26). Changes in blood and urine measures showed trends but no significant differences between groups (p > 0.05). In summary, the decline in a number of important measures of musculoskeletal and cardiovascular health was attenuated but not eliminated by a subject-specific program of locomotor exercise designed to replace daily load accumulated during free living. We conclude that single daily bouts of exposure to locomotor exercise can play a role in a countermeasures program during bed rest, and perhaps space flight, but are not sufficient in their own right to ensure musculoskeletal or cardiovascular health.

The efficacy and safety of Grafix(®) for the treatment of chronic diabetic foot ulcers: results of a multi-centre, controlled, randomised, blinded, clinical trial.

In a randomised, controlled study, we compared the efficacy of Grafix(®) , a human viable wound matrix (hVWM) (N = 50), to standard wound care (n = 47) to heal diabetic foot ulcers (DFUs). The primary endpoint was the proportion of patients with complete wound closure by 12 weeks. Secondary endpoints included the time to wound closure, adverse events and wound closure in the crossover phase. The proportion of patients who achieved complete wound closure was significantly higher in patients who received Grafix (62%) compared with controls (21%, P = 0·0001). The median time to healing was 42 days in Grafix patients compared with 69·5 days in controls (P = 0·019). There were fewer Grafix patients with adverse events (44% versus 66%, P = 0·031) and fewer Grafix patients with wound-related infections (18% versus 36·2%, P = 0·044). Among the study subjects that healed, ulcers remained closed in 82·1% of patients (23 of 28 patients) in the Grafix group versus 70% (7 of 10 patients) in the control group (P = 0·419). Treatment with Grafix significantly improved DFU healing compared with standard wound therapy. Importantly, Grafix also reduced DFU-related complications. The results of this well-controlled study showed that Grafix is a safe and more effective therapy for treating DFUs than standard wound therapy.

Clustering and classification of regional peak plantar pressures of diabetic feet.

High plantar pressures have been associated with foot ulceration in people with diabetes, who can experience loss of protective sensation due to peripheral neuropathy. Therefore, characterization of elevated plantar pressure distributions can provide a means of identifying diabetic patients at potential risk of foot ulceration. Plantar pressure distribution classification can also be used to determine suitable preventive interventions, such as the provision of an appropriately designed insole. In the past, emphasis has primarily been placed on the identification of individual focal areas of elevated pressure. The goal of this study was to utilize k-means clustering analysis to identify typical regional peak plantar pressure distributions in a group of 819 diabetic feet. The number of clusters was varied from 2 to 10 to examine the effect on the differentiation and classification of regional peak plantar pressure distributions. As the number of groups increased, so too did the specificity of their pressure distributions: starting with overall low or overall high peak pressure groups and extending to clusters exhibiting several focal peak pressures in different regions of the foot. However, as the number of clusters increased, the ability to accurately classify a given regional peak plantar pressure distribution decreased. The balance between these opposing constraints can be adjusted when assessing patients with feet that are potentially "at risk" or while prescribing footwear to reduce high regional pressures. This analysis provides an understanding of the variability of the regional peak plantar pressure distributions seen within the diabetic population and serves as a guide for the preemptive assessment and prevention of diabetic foot ulcers.

Custom therapeutic insoles based on both foot shape and plantar pressure measurement provide enhanced pressure relief.

OBJECTIVE: The purpose of this study was to determine whether custom insoles tailored to contours of the barefoot pressure distribution and shape of a patient's foot can reduce plantar pressures in the metatarsal head (MTH) region to a greater extent than conventional custom insoles. RESEARCH DESIGN AND METHODS: Seventy regions of elevated barefoot pressures (mean peak 834 kPa under MTHs) were identified in 20 subjects with diabetes. Foam box impressions of their feet were sent to three different orthotic supply companies for fabrication of custom insoles. One company was also given plantar pressure data, which were incorporated into the insole design. Measurements of in-shoe plantar pressures were recorded during gait for the three custom insoles in a flexible and a rocker-bottom shoe. Peak pressure and force-time integral were extracted for analysis. RESULTS: In 64 of 70 regions, the shape-plus-pressure-based insole in the flexible shoe achieved superior unloading compared with the two shape-based insoles. On average, peak pressure was reduced by 32 and 21% (both P

Nonsurgical strategies for healing and preventing recurrence of diabetic foot ulcers.

We have outlined an approach to the nonsurgical treatment of diabetic foot ulcers based on an understanding of their etiology. We have emphasized the importance of off-loading as the crucial element to success in healing foot ulcers and preventing their recurrence in those with diabetes. Computerized design of custom insoles can allow the unloading of elevated plantar pressure while incorporating the shape of the foot, which was formerly the major criterion used insole design.

Lower extremity strength plays only a small role in determining the maximum recoverable lean angle in older adults.

BACKGROUND: The purpose of this study was to determine the extent to which measures of lower extremity strength and power contribute to the ability of older men and women to restore postural equilibrium using a single-step recovery following a large postural disturbance. METHODS: The postural disturbance, which has been used as a surrogate for forward-directed falls, involved a sudden release from a forward-leaning angle. The ability to recover using a single step was evaluated as the maximum recoverable lean angle for 56 healthy older women and men. Maximum voluntary isometric and isokinetic strength was measured for ankle plantarflexion and dorsiflexion, knee flexion and extension, and hip flexion and extension. Discriminant analysis was used to determine the strength measures that best classified participants as members of the highest (n = 14) or lowest (n = 14) quartiles of maximum recoverable lean angle. Those variables were subsequently entered into a regression analysis to characterize the relationship between strength and maximum recoverable lean angle for the entire participant sample. RESULTS: Maximum isokinetic dorsiflexion strength at 90 degrees /s satisfied the criteria of the stepwise discriminant analysis, and correctly classified 82.1% of the participants in the highest or lowest quartiles of maximum recoverable lean angle. The multiple regression procedure, performed on all participants (n = 56) revealed a significant quadratic relationship between maximum isokinetic dorsiflexion strength at 90 degrees /s and maximum recoverable lean angle (R2 = 0.295; p <.001). CONCLUSIONS: Lower extremity strength makes a small, but significant contribution to maximum recoverable lean angle. However, because 70% of the shared variability remained unaccounted for, it is suggested that other performance factors, such as coordination, may be of greater importance to performance of this time-critical motor task.

Variability of step kinematics in young and older adults.

Fall-related injuries are the most common and serious medical problems facing older adults. Recent studies of older adults have focused on the variability of step kinematics and the relationship to falling. The accuracy of step variability estimates is proportional to the number of steps that are collected. The use of an instrumented treadmill allows simultaneous collection of spatial and temporal step kinematics for a large number of continuous steps. The current study was conducted to determine the influence of age, walking velocity and handrail use on the variability of step kinematics using a treadmill protocol. Eighteen young adults (average age: 27.7 +/- 3.3 years) and 12 healthy older adults (average age: 73.4 +/- 2.3 years) were recruited from the community. Temporal and spatial gait parameters were quantified using custom designed software from measurements collected during treadmill walking. The primary independent variables were the variability of step length, step width, and step time. Step width variability of older adults was significantly larger than that of young adults. Walking velocity did not influence step kinematic variability. Handrail usage influenced the variability of step length and step width, but not of step time. The present results, and those of previous studies, point to a consistent relationship between age and step width variability. Since step width variability has been implicated in falls, further research is warranted.

Step width variability, but not step length variability or step time variability, discriminates gait of healthy young and older adults during treadmill locomotion.

The variability of spatial and temporal step kinematics have separately been shown to prospectively predict falls by older adults. However, the published literature has not addressed the relative importance of the information related to locomotion control contributed by variability of spatial variables, temporal variables, or both. We conducted a post hoc analysis to determine the extent to which the variability of spatial and temporal step kinematics are independent descriptors of locomotion control in healthy young and older adults. A second purpose of the analysis was to establish the extent to which treadmill walking mimics overground walking using a benchmark for step kinematics. Eighteen young adults and 12 older adults walked at a self-selected velocity on an instrumented treadmill from which step length variability, step width variability and step time variability were computed. Stepwise discriminant analysis correctly classified group membership of 70 percent of the 30 subjects (i.e., young or older adult) using only step width variability (p=0.037, Wilk's lamda=0.854). Step width variability was 70+/-57 percent larger than step length variability (p<0.001). This relationship was similar to that of the benchmark established for overground locomotion. The results suggest that for healthy younger and older adults step width variability is a more meaningful descriptor of locomotion control than step length variability and step time variability. Given the potential clinical impact, further systematic study and improvement of the methods and technology for acquiring step kinematic data are warranted.

Influence of ball velocity, attention, and age on response time for a simulated catch.

PURPOSE: The ability of a baseball infielder to respond to a batted ball may provide the best defense for avoiding injury. This study investigated the response times of young athletes performing a simulated baseball-fielding task to estimate the maximum velocity with which a baseball can leave the bat and allow a player, standing 13.7 m away, to safely respond to the approaching ball. METHODS: Fifty boys and 50 girls between the ages of 8 and 16 yr participated. Baseballs were projected at the subjects who were standing in a standardized position behind a safety net. Two components of response time, reaction time and movement time, were determined using a motion capture system. The influences of baseball velocity (26.8 and 33.5 m.s(-1) and level of attention (full attention and attention splitting) on response time for a simulated baseball-fielding task were characterized. Based on the response times for each age group, the maximum exit-velocity from a baseball-bat interaction that would allow a young baseball player sufficient time to safely respond to an approaching baseball was calculated. RESULTS: The results showed that subjects had sufficient time to respond to exit-velocities from 26.8 m.s-1 (8- to 9-yr-old group) to 33.5 m.s-1 (16-yr-old group). However, the accuracy of the response was negatively affected by baseball velocity. CONCLUSIONS: If the exit-velocities seen during actual competition exceed the calculated maximum exit-velocities for these age groups, then our preliminary data suggest that modifications to the game of baseball that would reduce the actual exit-velocities and serve as an effective means to reduce the potential for serious or catastrophic injury are warranted.

Measuring step kinematic variability on an instrumented treadmill: how many steps are enough?

Variability of step kinematics has been associated with falls by older adults. However, between-study differences with regard to the number of steps used to compute variability have varied by an order of magnitude. If the number of steps used to compute variability is too low there is the potential for a statistically spurious outcome. On the other hand, for subjects with mobility impairments a protocol requiring too many steps to estimate variability imposes an unnecessary burden on the subjects. We have determined the minimum number of steps needed to estimate the variability of spatial and temporal step kinematics. More than 700 steps were collected during level walking on an instrumented treadmill. Accurate estimation of step kinematic variability required at least 400 steps. The increased error in estimating the mean and standard deviations of the step kinematic variables with too few steps can impose an experimental cost with regard to statistical design considerations. The extent to which translation of these results can be made to the variability of spatial and temporal step kinematics collected during over-ground walking awaits further research.

Motor control of the vastus medialis oblique and vastus lateralis muscles is disrupted during eccentric contractions in subjects with patellofemoral pain.

BACKGROUND: Inappropriate control of the vastus medialis oblique and vastus lateralis muscles by the central nervous system can contribute to maltracking of the patella. HYPOTHESIS: The activation timing and amplitude of the vastus medialis oblique and vastus lateralis muscles will be different between normal subjects and patients with patellofemoral pain. STUDY DESIGN: Controlled laboratory study. METHODS: Subjects with patellofemoral pain and asymptomatic control subjects performed maximum voluntary knee extension contractions initiated from a flexed and an extended position. The activation timing and amplitude of the vastus lateralis and vastus medialis oblique muscles were quantified from the recorded electromyographic signals. RESULTS: There were no between-group differences in activation timing. The activation amplitude of the vastus medialis oblique and vastus lateralis muscles of the patellofemoral pain subjects was altered to the greatest extent during eccentric contractions and differed significantly from that of control subjects. CONCLUSIONS: The activation amplitudes of the vastus medialis oblique and vastus lateralis muscles of subjects with patellofemoral pain are consistent with a laterally tracking patella during eccentric contractions. CLINICAL RELEVANCE: The findings suggest the clinical importance of determining whether altered activation patterns are sensitive to rehabilitation, and, if so, if subjective reports of knee joint pain and function parallel changes in the activation patterns as a result of rehabilitation.

Influence of lower extremity strength of healthy older adults on the outcome of an induced trip.

OBJECTIVES: To determine whether decreased lower extremity strength contributes to trip-related falls in older adults. DESIGN: A cross-sectional sample of older adults were safety-harnessed and tripped while walking using a concealed, mechanical obstacle. Lower extremity strength was compared between trip outcome groups. SETTING: A biomechanics research laboratory. PARTICIPANTS: Seventy-nine healthy, community-dwelling adults aged 65 and older (50 women). MEASUREMENTS: Ankle, knee, and hip flexion and extension strength were measured isometrically and isokinetically. Measured strengths were subjected to a factor analysis. Strength factor scores were compared between those who recovered from the trip and those who fell by three previously identified mechanisms: during-step, after-step, and elevating-response falls. RESULTS: Seven common factors, one associated with each direction of exertion at each joint and one with the time rate of moment increase, explained 88% of the variance in measured strength. The during-step (n=5) fallers were significantly stronger in the ankle extension (plantarflexion), knee flexion, overall extension, and total strength factors than those who successfully recovered using a similar, lowering strategy (n=26). The elevating-response faller (n=1) was stronger in the plantarflexion and overall extension factors than most of those who recovered using a similar, elevating strategy (n=11). Two of three after-step fallers were among the weakest subjects tested. CONCLUSION: Weak older adults and the strongest older adults may be at greater risk of falling from a trip, although by different mechanisms. High strength may increase the likelihood of a during-step or elevating-response fall; decreased strength may increase the likelihood of an after-step fall.