Market approval processes for new types of spinal devices: challenges and recommendations for improvement.

BACKGROUND: Spinal pathology and related symptoms are among the most common health problems and are associated with high health care costs and productivity losses. Due to the aging population, these costs are further increasing every year. Another important reason for the increasing costs is the market approval of new technologies, such as spinal devices that are usually more expensive than the existing technologies. Previous cases of medical device failure led to concern about possible deficiencies in the market approval process. OBJECTIVE: The objective is to provide an overview of U.S. Food and Drug Administration (FDA) regulation regarding spinal implants to delineate the challenges and opportunities that spine surgery currently faces. METHODS: In this paper, two cases of market entries of spinal devices are presented and evaluated to illustrate these deficiencies. RESULTS: Spinal implant regulation is facing several challenges. New spinal devices should increase patient outcomes and safety at reasonable societal costs. The main challenge is to have a rigorous evaluation before dissemination, while still leaving room for innovative behavior that thrusts the healthcare practice forward. CONCLUSION: We have provided recommendations to enhance spinal implant regulation and improve and ensure the patient's safety and the future of spine surgery.

Temperature control with internally applied cooling in solid material drilling: an experimental, biomechanical study.

PURPOSE: The purpose of this study was to evaluate the different temperature levels while drilling solid materials and to compare different cooling solutions for possible temperature control. An additional purpose was to develop an internal cooling device which can be connected to routinely used manual drilling devices in trauma surgery. METHODS: Drilling was performed on a straight hip stem implanted in bovine femora without cooling, with externally applied cooling and with a newly developed internal cooling device. Temperature changes were measured by seven thermocouples arranged near the borehole. Additionally, thermographic scans were performed during drilling. RESULTS: Drilling without cooling leads to an immediate increase in temperature to levels of thermal osteonecrosis (over 200 °C). With externally applied cooling temperatures were decreased, but were still up to a tissue damaging 85 °C. Internally applied cooling led to a temperature decrease to tissue-preserving levels during the drilling procedure (24.7 °C). CONCLUSION: Internal cooling with HPC-drillers lowered the measured temperatures to non-tissue damaging temperatures and should avoid structural tissue damage.

In Silico Clinical Trials in the Orthopedic Device Industry: From Fantasy to Reality?

The orthopedic device industry relies heavily on clinical evaluation to confirm the safety, performance, and clinical benefits of its implants. Limited sample size often prevents these studies from capturing the full spectrum of patient variability and real-life implant use. The device industry is accustomed to simulating benchtop tests with numerical methods and recent developments now enable virtual "in silico clinical trials" (ISCT). In this article, we describe how the advancement of computer modeling has naturally led to ISCT; outline the potential benefits of ISCT to patients, healthcare systems, manufacturers, and regulators; and identify how hurdles associated with ISCT may be overcome. In particular, we highlight a process for defining the relevant patient risks to address with ISCT, the utility of a versatile software pipeline, the necessity to ensure model credibility, and the goal of limiting regulatory uncertainty. By complementing-not replacing-traditional clinical trials with computational evidence, ISCT provides a viable technical and regulatory strategy for characterizing the full spectrum of patients, clinical conditions, and configurations that are embodied in contemporary orthopedic implant systems.

Using the modified Ponseti method to treat complex clubfoot: Early results.

OBJECTIVES: This study aims to present the results of complex clubfoot patients treated with modified Ponseti method and put forth the warning clinical signs of complex deformities. PATIENTS AND METHODS: A total of 11 patients (10 males, 1 female; mean age 60.1±49.7; range, 2 to 180 days) with 16 complex clubfeet treated with modified Ponseti method were included in this study conducted between January 2016 and June 2019. All the data of the patients were collected prospectively and reviewed retrospectively. Demographic features, clubfoot severity, number of casts, position of each foot before cast removal, ankle dorsiflexion (DF), complications, and additional procedures were noted at all clinical visits. RESULTS: Eleven (11.2%) of 98 patients had complex clubfoot deformity. Six (7.7%) of 78 newly diagnosed patients and five (25%) of 20 referred patients had complex clubfeet. We treated 16 complex clubfeet of 11 patients. The mean follow-up period was 13.3 (range, 10 to 16) months. All deformities were initially corrected using a mean of seven (range, 5 to 8) casts and Achilles tenotomy. Relapses occurred in three (18.75%) patients, but all recovered after recasting. The creases above the heels disappeared in all of the patients, whereas plantar creases persisted on two (12.5%) feet. Pirani scores and DF improved statistically significantly after treatment, and DF improved significantly between tenotomy and the final visit. CONCLUSION: The modified Ponseti method is an effective treatment for complex clubfoot. Classical clinical appearance, treatment-resistant deformities and referred patients should be warning signs for complex clubfoot.

Correlation Between Conditional Approval and Customized Bone Implant Devices.

This report aims to summarize key concerns regarding customized devices and conditional approval during the premarket evaluation of bone implants, and to explore the correlation between them. Based on the experience of approval of the first domestic custom-designed bone implant, we consider the process of gaining conditional approval for urgently-needed medical devices and medical devices for rare diseases, as well as the guidance available for clinical investigation. We also streamlined the scientifically administrative concept of this unique device, from the design and development of premarket technical evaluation to continuous post-market study. The present study found that those two aspects have certain connections, but they are not directly correlated to each other. In contrast to the USA, Canada, Australia and the EU, where regulations and guidelines have been established for the use of customized devices, in this regard, China is still it its infancy. Thus, there is considerable potential for China to develop and perfect the policies relating to customized devices and to develop relevant strategies to ensure their efficacy with the aid of conditional approval. Appropriate scientific conditional approval for mass production of individualized anatomy-matching bone implants could become a valuable approach for precision medicine.

Comparing the Efficacy of Methods for Immobilizing the Cervical Spine.

STUDY DESIGN: This was a prospective simulator study with 16 healthy male subjects. OBJECTIVE: The aim of this study was to compare the relative efficacy of immobilization systems in limiting involuntary movements of the cervical spine using a dynamic simulation model. SUMMARY OF BACKGROUND DATA: Relatively few studies have tested the efficacy of immobilization methods for limiting involuntary cervical movement, and only one of these studies used a dynamic simulation system to do so. METHODS: Immobilization configurations tested were cot alone, cot with cervical collar, long spine board (LSB) with cervical collar and head blocks, and vacuum mattress (VM) with cervical collar. A motion platform reproduced shocks and vibrations from ambulance and helicopter field rides, as well as more severe shocks and vibrations that might be encountered on rougher terrain and in inclement weather (designated as an "augmented" ride). Motion capture technology quantitated involuntary cervical rotation, flexion/extension, and lateral bend. The mean and 95% confidence interval of the mean were calculated for the root mean square of angular changes from the starting position and for the maximum range of motion. RESULTS: All configurations tested decreased cervical rotation and flexion/extension relative to the cot alone. However, the LSB and VM were significantly more effective in decreasing cervical rotation than the cervical collar, and the LSB decreased rotation more than the VM in augmented rides. The LSB and VM, but not the cervical collar, significantly limited cervical lateral bend relative to the cot alone. CONCLUSION: Under the study conditions, the LSB and the VM were more effective in limiting cervical movement than the cervical collar. Under some conditions, the LSB decreased repetitive and acute movements more than the VM. Further studies using simulation and other approaches will be essential for determining the safest, most effective configuration should providers choose to immobilize patients with suspected spinal injuries. LEVEL OF EVIDENCE: 3.

Medical devices in orthopedic applications.

Orthopedic medical devices have been extremely successful in restoring mobility, reducing pain, and improving the quality of life for millions of individuals each year. Their success is reflected in the worldwide biomaterials market, in which orthopedic devices dominated sales at approximately $14 billion in 2002. Of this, approximately $12 billion was spent on joint replacements. In spite of their overwhelming benefits and successes, orthopedic medical devices are not without risk of adverse effects. Most adverse joint replacement outcomes are thought to be mediated by degradation products generated by wear and electrochemical corrosion. Infection and flaws in device manufacturing are other noteworthy causes of orthopedic device failure. This article illustrates and discusses the uses, general properties, and limitations (including adverse outcomes) of orthopedic biomaterials, which are fundamental to understanding requirements for improving current orthopedic medical devices.

Comparison of patellar mobility in female adults with and without patellofemoral pain.

STUDY DESIGN: Case control study. OBJECTIVE: To compare the patellar mobility of female adult subjects with and without patellofemoral pain (PFP). BACKGROUND: Although abnormal patellar mobility is believed to be one of the causes of PFP, there is currently no published evidence to support this contention. In part, this lack of evidence is because a reliable clinical measurement method to measure patellar mobility and objective criteria to define abnormal patellar mobility have not been established. METHODS AND MEASURES: The study sample was comprised of 22 females with PFP (PFP group) and 22 females who had no knee pain (control group), matched by age, height, and body mass index to the subjects with PFP. Patellar mobility was measured objectively using a specially designed apparatus. Measurements of lateral and medial patellar displacement, patellar mobility balance (lateral minus medial patellar displacement), lateral patellar mobility index (lateral patellar displacement divided by patellar width), and medial patellar mobility index (medial patellar displacement divided by patellar width) were used. RESULTS: Lateral and medial patellar mobility values were not significantly different between the individuals in the PFP and control groups. When normal patellar mobility was arbitrarily defined as the average mobility +/- 2 SDs, based on the data from the control group, normal lateral patellar displacement was within a range of 7.2 to 17.6 mm and normal medial patellar displacement was within a range of 6.8 to 14.0 mm. The intraclass correlation coefficient for intratester and intertester reliability of lateral and medial patellar displacement measurements varied from 0.80 to 0.97. CONCLUSION: Although there were no significant differences in patellar mobility between females with and without PFP, these measurements give reference information about normal patellar mobility for this group. LEVEL OF EVIDENCE: Diagnosis, level 5.

Decreasing an Offloading Device's Size and Offsetting Its Imposed Limb-Length Discrepancy Lead to Improved Comfort and Gait.

OBJECTIVE: Patient adherence is a challenge in offloading diabetic foot ulcers (DFUs) with removable cast walkers (RCWs). The size and weight of an RCW, changes to gait, and imposed limb-length discrepancies may all discourage adherence. This study sought to determine whether RCW size and provision of a contralateral limb lift affected users' comfort and gait. RESEARCH DESIGN AND METHODS: Twenty-five individuals at risk for DFUs completed several 20-m walking trials under five footwear conditions: bilateral standardized shoes, a knee-high RCW with shoe with or without an external shoe lift contralaterally, and an ankle-high RCW with shoe with or without an external shoe lift contralaterally. Perceived comfort ratings were assessed through the use of visual analog scales. Spatial and temporal parameters of gait were captured by an instrumented walkway, and plantar pressure was measured and recorded using pedobarographic insoles. RESULTS: The bilateral shoes condition was reported to be most comfortable; both RCW conditions without the lift were significantly less comfortable (P < 0.01). In contrast to the ankle-high RCW, the knee-high RCW resulted in significantly slower walking (5.6%; P < 0.01) but greater offloading in multiple forefoot regions of the offloaded foot (6.8-8.1%; P < 0.01). Use of the contralateral shoe lift resulted in significantly less variability in walking velocity (52.8%; P < 0.01) and reduced stance time for the offloaded foot (2.6%; P = 0.01), but it also reduced offloading in multiple forefoot regions of the offloaded foot (3.7-6.0%; P < 0.01). CONCLUSIONS: Improved comfort and gait were associated with the ankle-high RCW and contralateral limb lift. Providing this combination to patients with active DFUs may increase offloading adherence and subsequently improve healing.

Reference marker stability in computer aided orthopedic surgery: a biomechanical study in artificial bone and cadavers.

INTRODUCTION: In computer assisted orthopaedic surgery, rigid fixation of the Reference Marker (RM) system is essential for reliable computer guidance. A minimum shift of the RM can lead to substantial registration errors and inaccuracies in the navigation process. Various types of RM systems are available but there is little information regarding the relative stabilities of these systems. The aim of this study was to test the rotational stability of three commonly used RM systems. MATERIALS AND METHODS: One hundred and thirty Synbones and 15 cadavers were used to test the rotational stability of three different RM systems (Schanz' screw, RM B and RM C adjustment systems). Using a specially developed testing device, the peak torque sustained by each RM system was assessed in various anatomical sites. RESULTS: Comparison of means for Synbone showed that the RM C was the most stable (mean peak torque 5.60 +/- 1.21 Nm) followed by the RM B system (2.53 +/- 0.53 Nm) and the RM A (0.77 +/- 0.39 Nm) (p<0.01). The order of stability in relation to anatomical site was femoral shaft, distal femur, tibial shaft, proximal tibia, anterior superior iliac spine, iliac crest and talus. Results from the cadaver experiments showed similar results. Bi-cortical fixation was superior to mono-cortical fixation in the femur (p<0.01) but not the tibia (p=0.22). CONCLUSION: The RM system is the vital link between bone and computer and as such the stability of the RM is paramount to the accuracy of the navigation process. In choosing RM systems for computer navigated surgery surgeons should be aware of their relative stability. Anatomical site of RM placement also affect the stability. Mono-cortical fixation is generally less stable than bi-cortical.

Gait rehabilitation: a new biofeedback device for monitoring and enhancing weight-bearing over the affected lower limb.

AIM: Gait rehabilitation programs often require either partial weight-bearing (PWB) or encourage full weight-bearing (FWB) on the affected limb. Until recently, there was no objective and practical way to measure correct weight-bearing during ambulation. The present study evaluates a new in-shoe device (SmartStep, Andante Medical Devices Ltd.) for measuring the amount of weight on the affected limb and for biofeedback gait training. METHODS: The first part of the study aimed to establish the validity of the SmartStep by comparing the results obtained from this device with the results obtained from a force plate. The second part aimed to evaluate the effectiveness of the SmartStep as a biofeedback method in patients who have been referred for FWB gait rehabilitation. Analysis was based on independent samples t-test and chi squared test for evaluating statistically significant differences between the 2 gait rehabilitation modes. RESULTS: The SmartStep could repeat the same results with 0.53 kg error of mean. Statistically significant correlation was found between results obtained from the SmartStep and from the force plate (R2=0.9067 and P=0.004). The use of the SmartStep auditory biofeedback, significantly (P=0.00031) improved patients' weight-bearing over the affected limb in the experimental group (7.9 kg +/-5.28) as compared to the control group (0.7+/-2.41 kg). CONCLUSIONS: The SmartStep proved to be very reliable since it generated significant repeatable results which correlated significantly with those obtained from a force plate. Patients recommended for FWB gait can significantly improve body weight loading over the affected limb by the use of the SmartStep auditory biofeedback.

Spinal devices in the United States-investigational device exemption trials and premarket approval of class III devices.

BACKGROUND CONTEXT: Recently, there has been increased public awareness of regulatory actions by the United States Food and Drug Administration (FDA) on spinal devices. There has also been increased scrutiny of the pivotal clinical trials of these devices. PURPOSE: To investigate the premarket approval (PMA) of class III spinal devices in the United States since the turn of the century. To explore clinically relevant issues that affect the interpretation of investigational device exemption trials. STUDY DESIGN: Literature review. METHODS: From 2000 to 2015, data on PMA applications for spinal devices were obtained from two sources. First, meetings of FDA's Orthopaedic and Rehabilitation Devices Panel were identified from the Federal Register. Second, the FDA database of approved PMA applications was queried. For each device, two authors reviewed all archival data. There was no external source of funding. RESULTS: Twenty-one devices met the study criteria. There were 76.2% that received approval and 47.6% that went to panel. Arthroplasty devices were most common (52.4%), least likely to go to panel (3 of 11), and most likely to be approved after panel (3 of 3). Biologic devices were most likely to go to panel (3 of 3) and least likely to be approved after panel (1 of 3). Before and after 2009, there was no decrease in the number of spinal devices approved. All 21 devices were studied in a pivotal clinical trial. All trials except one were randomized controlled trials, and all trials except one were two-arm noninferiority designs. CONCLUSIONS: There has been no decrease in the number of new FDA-approved class III spinal devices since the turn of the century. The majority of devices have been for cervical arthroplasty. By contrast, biologic devices were most likely to go to panel and least likely to be approved after panel. The pivotal trials for nearly all devices were randomized, two-arm, noninferiority trials.

Taking a Concept to Commercialization: Designing Relevant Tests to Address Safety.

Taking a product from concept to commercialization requires careful navigation of the regulatory pathway through a series of steps: (A) moving the idea through proof of concept and beyond; (B) evaluating new technologies that may provide added value to the idea; (C) designing appropriate test strategies and protocols; and (D) evaluating and mitigating risks. Moving an idea from the napkin stage of development to the final product requires a team effort. When finished, the product rarely resembles the original design, but careful steps throughout the product life cycle ensure that the product meets the vision.

The validity and reliability of the Klaue device.

BACKGROUND: Excessive first ray mobility has been implicated as the cause of many forefoot abnormalities. The association between hypermobility and forefoot pathology is controversial, and this is largely related to the difficulty in quantifying first ray motion. Manual examinations have been shown to be unreliable. Klaue etal. developed a device consisting of a modified ankle-foot orthosis with an attached micrometer to objectively measure first ray mobility. The purpose of this study was to evaluate the validity and reliability of this device. METHODS: Sixteen fresh-frozen, below-knee amputation specimens with hallux valgus were used for the study. The study was divided into two parts. Part I was an analysis of the validity of the Klaue device; first ray dorsal displacement was measured on lateral radiographs following manual manipulation, and values were statistically compared to the Klaue device measurements. Part II of the study was an evaluation of intraobserver and interobserver agreement. Two clinicians used the Klaue device on each of the cadaver limbs, and values of first ray sagittal mobility were recorded and compared. RESULTS: The mean value of first ray mobility measured with the Klaue device was 7.5 mm and the average displacement measured from the lateral radiographs was 7.4 mm. Paired t-testing showed no significant difference between the Klaue and radiographic measurements (p = 0.83). The mean first ray mobility by examiners 1 and 2 with the Klaue device were identical (10.5 mm), and statistical analysis showed no significant interobserver or intraobserver differences. CONCLUSIONS: The results confirm the validity of the Klaue device and limited variability of measurements between experienced users.

A comparison of device measures of dorsal first ray mobility.

BACKGROUND: Devices built by Glasoe and Klaue have been used in several studies to measure first ray mobility. Both devices measure sagittal motion of the first ray in a dorsal direction. The primary difference in the devices is the method of the load imposed. This study investigates whether first ray mobility measured with the Glasoe device is similar to the amount of mobility measured with the Klaue device. METHODS: Using the devices described by Glasoe and Klaue, dorsal first ray mobility was measured in 39 patients who had foot and ankle problems. Paired t-tests were computed to assess for differences between device measures of dorsal mobility. Intraclass correlation coefficient (ICC) and absolute difference values were computed to further assess the agreement in measures. RESULTS: Dorsal mobility measured with the Glasoe device averaged 4.9 mm (1.8 to 9.3 mm). Dorsal mobility measured with the Klaue device averaged 5.2 mm (2.5 to 8.5 mm). Paired t-tests (p = 0.12) revealed no significant difference in measures. An ICC of 0.70 and a mean absolute difference of 0.9 mm (SD 0.8) were found between the two clinical measures further suggesting agreement. CONCLUSION: Results indicated that the two devices possess similar diagnostic accuracy in the measurement of dorsal first ray mobility.

Quantification of muscle strength and imbalance in neurogenic pes cavus, compared to health controls, using hand-held dynamometry.

BACKGROUND: Pes cavus foot deformity in neuromuscular disease is thought to be related to an imbalance of musculature around the foot and ankle. The most common cause of neurogenic pes cavus is Charcot-Marie-Tooth (CMT) disease. The aim of this investigation was to objectively quantify muscle strength and imbalance using hand-held dynamometry in patients diagnosed with CMT and pes cavus, compared to healthy controls. METHODS: Muscles responsible for inversion, eversion, plantarflexion, and dorsiflexion of the foot and ankle were measured in 55 subjects (11 CMT patients with a frank pes cavus, and 44 healthy controls with normal feet) using the Nicholas hand-held dynamometer (HHD). Test-retest reliability of the HHD procedure also was determined for each of the four muscle groups in the healthy controls. RESULTS: Test-retest reliability of the HHD procedure was excellent (ICC3,1 = 0.88 to 0.95) and the measurement error was low (SEM = 0.3 to 0.7 kg). Patients with CMT were significantly weaker than normal for all foot and ankle muscle groups tested (p < 0.001). Strength ratios of inversion-to-eversion and plantarflexion-to-dorsiflexion were significantly higher in the patients with CMT and pes cavus compared to individuals with normal foot types (p > 0.01). CONCLUSIONS: Hand-held dynamometry is an objective and reliable instrument to measure muscle strength and imbalance in patients with CMT and a pes cavus foot deformity.

Reliability of foot caliper.

OBJECTIVES: To determine the reliability of foot caliper DESIGN: Descriptive study. SETTING: Rehabilitation Medicine Outpatient Department, King Chulalongkorn Memorial Hospital. SUBJECT: Fifteen volunteers were recruited from Rehabilitation residents and health care professionals of Department of Rehabilitation Medicine, King Chulalongkorn Memorial Hospital. MATERIAL AND METHOD: The authors created 3 sets of simple Foot Caliper and measured foot dimension including foot width, foot length and toe depth while subjects stood with equal weight bearing to both feet. The authors set 3 examiners to measure foot dimension by the same method. To determine reliability of 3 sets of foot caliper, one examiner was assigned to measure foot dimension of 30 feet with all calipers. To determine the reliability of examiners, all examiners measured foot dimension of the same 30 feet. All parameters were recorded in millimeters. The data was analyzed and presented as intraclass correlation coefficients (ICC) with 95% CI. RESULTS: There were fifteen volunteers (8 men and 7 women). The average age was 28.6 +/- 4.11 years (range 22-39). Average foot width,length and great toe depth (millimeters) were 9.64 +/- 0.63, 24.17 +/- 1.10 and 1.91 +/- 0.24 respectively. For reliability analysis of 3 sets off foot caliper, the intraclass correlation coefficients (ICC) with 95% CI were 0.985 (0.972-0.992), 0.996 (0.992-0.998) and 0.982 (0.968-991) for foot width, length and great toe depth, respectively. For Inter-examiner reliability, intraclass correlation coefficients (ICC) were 0.941 (0.864-0.969), 0.850 (0.46-0.920) and 0.834 (0.721-0.910) for foot width, length and great toe depth, respectively. These results showed high agreement of data. CONCLUSION: These simple foot calipers have high reliability forf oot measurement. These devices are appropriate for clinical use.

[The introduction of new medical devices]. / De introductie van nieuwe medische implantaten.

Regulation of the introduction of new or improved medical devices is fundamentally different from that of new drugs and is inadequate in its current form. This was recently demonstrated by large-scale problems with medical devices in various specialist fields. Steps have been taken by scientific professional associations, regulating authorities and industry to prevent these problems from happening in the future. However, these steps have not yet been implemented or have not been sufficiently well implemented, and have not been completely coordinated. The practitioner therefore needs to remain extremely critical when using new medical devices.

The influence of the size and condition of the reamers on bone temperature during intramedullary reaming.

BACKGROUND: The objectives of this study were to determine whether intramedullary reaming increases bone temperature in vivo to a level that is high enough to produce bone necrosis and to determine the influence of the size and the condition of the reamers on the temperature increase. METHODS: Bone temperature variations were recorded in vivo during intramedullary tibial reaming in fourteen minipigs. The left tibiae were progressively reamed from 6 to 9 mm. The right tibiae were reamed with only 8 and 9-mm reamers. The variables studied were the initial and final temperature and the increase in the temperature. Two weeks after reaming, the tibiae were removed and studied histologically. RESULTS: Intramedullary reaming produced an average increase (and standard deviation) in bone temperature of 6.9 degrees C +/- 4.1 degrees C. The peak temperatures ranged from 34.9 degrees C to 49.4 degrees C. The average maximum bone temperature was 38.1 degrees C +/- 2.8 degrees C when the reaming was done progressively from 6 to 9 mm and 41.1 degrees C +/- 4.4 degrees C when the reaming was done only with the 8 and 9-mm reamers. The mean increase in the temperature in the second group of animals (8.2 degrees C +/- 4.3 degrees C) was greater than that in the first group (5.4 degrees C +/- 3.5 degrees C). Reaming with sharper reamers in the first seven animals resulted in a smaller mean increase in temperature than did reaming with less sharp reamers in the last seven animals (4.6 degrees C compared with 9.2 degrees C; p = 0.001). Histological examination of the tibiae showed periosteal proliferation and an altered disposition of the osteons at the inner cortex with occasional necrotic bone fragments in the medullary canal. CONCLUSIONS: Intramedullary reaming in the minipig increased bone temperature. When the reamer initially used was larger than the diameter of the medullary canal and when the reamers were blunted by repeated use, the maximum temperature reached by the bone was higher. This increase in temperature with use of typical medullary reaming techniques did not exceed the limits that would produce bone necrosis.