Bioequivalence trials for the approval of generic drugs in Saudi Arabia: a descriptive analysis of design aspects.

BACKGROUND: This retrospective analysis aimed to comprehensively review the design and regulatory aspects of bioequivalence trials submitted to the Saudi Food and Drug Authority (SFDA) since 2017. METHODS: This was a retrospective, comprehensive analysis study. The Data extracted from the SFDA bioequivalence assessment reports were analyzed for reviewing the overall design and regulatory aspects of the successful bioequivalence trials, exploring the impact of the coefficient of variation of within-subject variability (CVw) on some design aspects, and providing an in-depth assessment of bioequivalence trial submissions that were deemed insufficient in demonstrating bioequivalence. RESULTS: A total of 590 bioequivalence trials were included of which 521 demonstrated bioequivalence (440 single active pharmaceutical ingredients [APIs] and 81 fixed combinations). Most of the successful trials were for cardiovascular drugs (84 out of 521 [16.1%]), and the 2 × 2 crossover design was used in 455 (87.3%) trials. The sample size tended to increase with the increase in the CVw in trials of single APIs. Biopharmaceutics Classification System Class II and IV drugs accounted for the majority of highly variable drugs (58 out of 82 [70.7%]) in the study. Most of the 51 rejected trials were rejected due to concerns related to the study center (n = 21 [41.2%]). CONCLUSION: This comprehensive analysis provides valuable insights into the regulatory and design aspects of bioequivalence trials and can inform future research and assist in identifying opportunities for improvement in conducting bioequivalence trials in Saudi Arabia.

A literature review and expert consensus statement on diagnostics in suspected metal implant allergy.

BACKGROUND: Although rare, allergic reactions to metal implants represent a diagnostic challenge in view of missing guidelines. OBJECTIVES: To develop an European expert consensus on characteristics of metal allergy reactions and the utility of various diagnostic tools in suspected metal implant allergy. METHODS: A nominal group technique (NGT) was applied to develop consensus statements. Initially an online literature database was created on a secure server to enable a comprehensive information. Twenty-three statements were formulated on potential aspects of metal implant allergy with a focus on diagnostics and grouped into five domains. For the consensus development, the panel of 12 experts initially did refine and reformulate those statements that were ambiguous or had unclear wording. By face-to-face (9/12) or virtual participation (3/12), an anonymous online voting was performed. RESULTS: Consensus (≥80% of agreement) was reached in 20/23 statements. The panel agreed that implant allergy despite being rare should be considered in case of persistent unexplained symptoms. It was, however, recommended to allow adequate time for resolution of symptoms associated with healing and integration of an implant. Obtaining questionnaire-aided standardized medical history and standardized scoring of patient outcomes was also considered an important step by all experts There was broad consensus regarding the utility/performance of patch testing with additional late reading. It was recognized that the lymphocyte transformation test (LTT) has to many limitations to be generally recommended. Prior to orthopaedic implant, allergy screening of patients without a history of potential allergy to implant components was not recommended. CONCLUSIONS: Using an expert consensus process, statements concerning allergy diagnostics in suspected metal implant allergy were created. Areas of nonconsensus were identified, stressing uncertainty among the experts around topics such as preoperative testing in assumed allergy, histological correlate of periimplant allergy and in vitro testing, which underscores the need for further research.

Invasive electrical stimulation in the treatment of avascular osteonecrosis of the femoral head - mid-term results.

The study aimed to evaluate the outcomes of osteonecrosis of the femoral head (ONFH) in adults after surgical treatment including invasive electromagnetic osteostimulation (E-Stim). Further, the influence of disease stage and several comorbidities on the joint preservation rate should be examined. Sixty patients (66 hip joints) with ONFH were included in this retrospective cross-sectional analysis (mean follow-up: 58 months, 19-110 months). Potential ONFH risk factors and comorbidities (ONFH stage, age, sex, alcohol, smoking, cortisone medication, chemotherapy) were recorded. The influence of specific parameters on the joint preservation rates was evaluated by a multivariate logistic regression analysis. Finally, patients with preserved hip joints underwent an assessment of their last available X-rays. The joint preservation rate depended on the initial ONFH Steinberg stage (I+II: 82.8%, III: 70.8%, ≥ IVa: 38.5%). Initially collapsed ONFH (p ≤ 0.001) and cortisone therapy (p = 0.004) significantly decreased the joint preservation rates. In case of progressed ONFH, the presence of ≥ 2 risk factors resulted in higher THA conversion rates (stage III: OR 18.8; stage ≥IVa: OR 12). In 94% of the available X-rays, the ONFH stage improved or did not progress. No complications could be attributed to the E-Stim device or procedure. The present surgical protocol including minimally invasive E-Stim revealed high joint preservation rates for non-collapsed ONFH after mid-term postoperative follow-up. Especially in progressed ONFH, the-risk profile seems to be crucial and hence, for joint preserving surgery, careful patient selection is recommended.

Folate/Vitamin B12 Supplementation Combats Oxidative Stress-Associated Carcinogenesis in a Rat Model of Colon Cancer.

Folate and vitamin B12 deficiency is associated with depletion of the major intracellular antioxidant glutathione, and oxidative stress is emerging as an etiological mechanism for colon cancer. Azoxymethane (AOM), a potent carcinogen, induces colon cancer in rats by causing pathophysiological changes and oxidative stress. We investigated the synergistic effect of folate and vitamin B12 supplementation against AOM-induced carcinogenesis and oxidative stress in rat colon. Adult male rats were distributed into four groups: 1) Basal diet only; 2) AOM injection (15 mg/kg once per week in weeks 5 and 6); 3) Folate and vitamin B12 supplemented diet; 4) Folate and B12 diet with AOM injection. After 16 weeks, rats were sacrificed, colon tissue dissected, indicators of oxidative stress were measured, and immunohistochemical and ultrastructural changes were evaluated. AOM-injected rats showed oxidative stress, evident by glutathione depletion, oxidation of cellular proteins, and DNA oxidative damage. AOM increased mucosal levels of antiapoptotic and proapoptotic proteins Bcl2 and Bax and caused ultrastructure changes in colonic cell organelles. Folate and vitamin B12 supplementation decreased the level of oxidative stress and ameliorated the cytotoxic effects of AOM. In this in vivo experimental model of colon cancer, folate and vitamin B12 supplementation combats carcinogen-induced oxidative stress.

Predictors of colonization with Staphylococcus species among patients scheduled for cardiac and orthopedic interventions at tertiary care hospitals in north-eastern Germany-a prevalence screening study.

As methicillin-resistant Staphylococcus aureus (MRSA) colonization and infection in humans are a global challenge. In Mecklenburg and Western Pomerania (Germany) 1,517 patients who underwent surgical interventions were systematically screened for MRSA and MSSA colonization on the day of hospital admission and discharge. Demographic data, risk factors and colonization status of the (i) nose, (ii) throat, (iii) groin, and (iv) thorax or site of surgical intervention were determined. Of the 1,433 patients who were included for further evaluation, 331 (23.1%) were colonized with MSSA, while only 17 (1.2%) were MRSA carriers on the day of hospital admission. A combination of nose, throat and groin swabs returned a detection rate of 98.3% for MSSA/MRSA. Trauma patients had lower prevalence of MRSA/MSSA (OR 0.524, 95% CI: 0.37-0.75; p < 0.001) than patients with intended orthopedic interventions. Males showed significantly higher nasal S. aureus carrier rates than females (odds ratio (OR) = 1.478; 95% CI: 1.14-1.92; p = 0.003). Nasal S. aureus colonization was less frequent among male smokers as compared to non-smokers (chi2 = 16.801; phi = 0.154; p < 0.001). Age, gender and smoking had a significant influence on S. aureus colonization. Combining at least three different swabbing sites should be considered for standard screening procedure to determine S. aureus colonization at patients scheduled for cardiac or orthopedic interventions at tertiary care hospitals.

The IGFBP7 homolog Imp-L2 promotes insulin signaling in distinct neurons of the Drosophila brain.

In Drosophila, Insulin-like peptide 2 (Dilp-2) is expressed by insulin-producing cells in the brain, and is secreted into the hemolymph to activate insulin signaling systemically. Within the brain, however, a more local activation of insulin signaling may be required to couple behavioral and physiological traits to nutritional inputs. We show that a small subset of neurons in the larval brain has high Dilp-2-mediated insulin signaling activity. This local insulin signaling activation is accompanied by selective Dilp-2 uptake and depends on the expression of the Imaginal morphogenesis protein-late 2 (Imp-L2) in the target neurons. We suggest that Imp-L2 acts as a licensing factor for neuronal IIS activation through Dilp-2 to further increase the precision of insulin activity in the brain.

Predictors of adherence to antihypertensive medication in northern United Arab Emirates.

This study aimed to assess the predictors of non-adherence to antihypertensive medications in northern United Arab Emirates. In a cross-sectional, multicentre study in Ajman Emirate, 250 patients with hypertension were randomly selected from outpatient clinics. Participants answered an interview questionnaire about sociodemographic and clinical data and completed the Morisky medication adherence scale. Non-adherence to antihypertensive medication was reported by 45.6% of patients. Sociodemographic predictors of non-adherence were sex and number of children. Therapy-related predictors of adherence were hospital admissions, number and cost of medications, medication perceived effectiveness and use of traditional remedies. Patient-related predictors of non-adherence were forgetfulness, method of identifying medication and poor awareness of hypertension complications. Health-care-related predictors were regular follow up at clinics, education and counselling, frequency of changing medication by physicians and awareness of physicians' instructions.

[Influence of surgeon experience in total hip arthroplasty. Dependence on operating time and complication risk]. / Einfluss der Erfahrung des Operateurs in der Hüftendoprothetik. Abhängigkeit von Operationsdauer und Komplikationsrisiko.

BACKGROUND: As a consequence of limited personnel and financial resources, the increase in total hip arthroplasties places higher demands on orthopedic surgeons. OBJECTIVES: In order to maintain high quality treatment, the correlation between surgical experience, duration of surgery and risk of complications was examined. MATERIAL AND METHODS: The surgery time and, if applicable, complications (until discharge from hospital) of 1129 total hip arthroplasties over a period of 4 years were evaluated retrospectively. RESULTS: The group of most experienced surgeons needed an average time of 53.2 ± 17.6 min for each implantation, followed by moderately experienced surgeons (74.5 ± 25.5 min) and less experienced surgeons (80.8 ± 21.9 min). Of all included cases, a total of 41 complications until discharge from hospital occurred. The number of complications increased with duration of surgery, whereby the risk of complications was significantly lower for shorter surgery times conducted by the most experienced surgeons as well as moderately experienced surgeons. The complication risk of less experienced surgeons remained constant independent of surgery duration. CONCLUSION: These results underline the recommendations of the German Endocert system, which determine a minimum number of total joint arthroplasties as a quality indicator not only for hospitals but also for individual surgeons.

[Failure analysis as basis for quality assurance strategies in implant technology]. / Schadensanalyse als Basis für Qualitätssicherungsstrategien in der Implantattechnologie.

BACKGROUND: Implant safety is a topic gaining more and more public interest. Implants are safety relevant medical devices which in the case of failure can lead to life-threatening situations. OBJECTIVES: A well-founded failure analysis requires expert knowledge not only of materials and implant design but also a qualified explantation procedure and storage conditions. METHODS: A selective literature search was carried out putting the main emphasis on implant failure analysis supplemented with own investigations. RESULTS: The reasons for implant breakdown are mostly failures of materials and in the manufacturing process. In some cases false material combinations can lead to tribocorrosion effects under cyclic loading. CONCLUSION: The increased level of knowledge gained from complex analyses of failed implants produces valuable evidence for better quality management.

[Reimbursement in psychiatry and psychosomatics: proof of concept for a system based on daily costs]. / Vergütungssystem für Psychiatrie und Psychosomatik: Studie zur Machbarkeit eines tageskostenbasierten Entgeltsystems.

BACKGROUND: In Germany a new reimbursement system for psychiatry and psychosomatics is under development. Based on total costs of each case from selected hospitals and day clinics, in 2013 the Institute for the Hospital Remuneration System (InEK) proposed to reimburse the hospital costs daily with step-wise decreasing remuneration, mainly depending on the ICD-10 diagnosis, duration of stay and some complicating factors (PEPP grouper). It is controversial whether this degressive system will result in an inadequate remuneration of patients with longer duration of severe symptoms, such as suicidality in depression or autoaggressive behavior in borderline personality disorder and will eventually lead to advantages for acutely ill patients with short duration of stay compared to chronically ill patients. OBJECTIVES: This study formulated and tested an alternative remuneration system (proof of concept) mainly based on an analysis of daily cost data instead of the total costs of each case. MATERIAL AND METHODS: The study is based on 147,749 treatment days from 4,633 cases of patients with psychotic disorders (PEPP-PA03) in 6 hospitals. As possible cost separating factors the study analyzed days with and without intensive psychiatric care, 1 to 1 care, psychological diagnostics, magnetic resonance imaging (MRI), acute crisis intervention, age at admission, the first days of treatment and day of discharge. RESULTS AND DISCUSSION: Nearly all factors tested were shown to be statistically significant in separating daily hospital costs. Based on these findings an alternative calculation algorithm (TEPPconcret), which grouped the cases with respect to age, intensive care, 1 to 1 care, treatment days 1-4 and day of discharge, was formulated and tested. For psychotic disorders TEPPconcret with a basic rate complemented by daily add-on payments depending on the effort involved, is a serious alternative to the PEPP system and awaits further evaluation.

Polychrome Bone Fluorescence: A valuable diagnostic tool for 4th degree calvarial burns. A Case report.

4th degree calvarial burns are complex in management with regards to determining bone vitality and subsequent choice of defect coverage. Distinguishing viable and nonviable bone can be challenging. Tetracycline bone fluorescence is well described and in common use in maxillofacial patients with bisphosphonate osteonecrosis and has been reported in septic orthopedic surgery specifically periprosthetic joint infection. On the basis that viable bone fluoresces, the concept of polychrome fluorescence was extrapolated as a diagnostic tool for calvarial burns. Bone fluorescence presents an efficient, non-invasive, and cost-effective diagnostic tool delineating exact necrotic margins in 4th degree burns ensuring targeted bone sparing debridement. This report describes the use of polychrome bone fluorescence as an intra-operative tool including a single-centre case report with 4th degree calvarial burns.

Early Assessment of Impact of Increased Value Added Tax on Smoking Behaviors and Financing among Adult Smokers in Saudi Arabia.

Background: Cigarette smoking has been identified as most perilous risk factor for several health ailments. Increased price may discourage smoking habits. There is limited literature available on impact of price rise on smoking behaviors in Saudi Arabia, which is the fourth largest importer of cigarettes and this study assessed the impact of tax increase (in 2020) on smoking behaviors. Methods: A cross-sectional survey was carried out between July 2021 and December 2021.i.e.one year after new value added tax (VAT) system came into force. Data was collected with 14-item pretested questionnaire from 721 adult smokers in Al-Jouf Region of Saudi Arabia selected through stratified cluster ransom sampling. We measured effects of tax increase on smoking behaviors, its impact on decision to quit and perceived health improvements as outcome variables. Results: Nearly 40% of the respondents said that increased price lead them to smoke less number of cigarettes per day (P=0.000), decreased smoking improved their health in terms of breathing capacity, mood, ability to exercise and sleep in hierarchy. 67.4% of the participants are currently thinking of quitting smoking due to increased prices (P=0.001) and logistic regression models identified reduced smoking due to tax rise (Odds=5.68), improvement in health (Odds=2.94) and excess spending of above 20% (Odds=1.72) significantly associated with intentions to quit smoking. Conclusion: Increased price of cigarettes due to VAT significantly decreased smoking behaviors and has impact on smokers' decision to quit smoking. Future studies needed to assess the long-term effect of increased tax on smoking behaviors and its relapse.

Adenoviral transduction supports matrix expression of alginate cultured articular chondrocytes.

The present study examines the effects of adenoviral (Ad) transduction of human primary chondrocyte on transgene expression and matrix production. Primary chondrocytes were isolated from healthy articular cartilage and from cartilage with mild osteoarthritis (OA), transduced with an Ad vector and either immediately cultured in alginate or expanded in monolayer before alginate culture. Proteoglycan production was measured using dimethylmethylene blue (DMMB) assay and matrix gene expression was quantified by real-time PCR. Viral infection of primary chondrocytes results in a stable long time transgene expression for up to 13 weeks. Ad transduction does not significantly alter gene expression and matrix production if chondrocytes are immediately embedded in alginate. However, if expanded prior to three dimension (3D) culture in alginate, chondrocytes produce not only more proteoglycans compared to non-transduced controls, but also display an increased anabolic and decreased catabolic activity compared to non-transduced controls. We therefore suggest that successful autologous chondrocyte transplantation (ACT) should combine adenoviral transduction of primary chondrocytes with expansion in monolayer followed by 3D culture. Future studies will be needed to investigate whether the subsequent matrix production can be further improved by using Ad vectors bearing genes encoding matrix proteins.

Evaluation of antimicrobial effects of novel implant materials by testing the prevention of biofilm formation using a simple small scale medium-throughput growth inhibition assay.

Staphylococcal colonization of implants is a serious complication of orthopaedic surgery. Anti-infectious modification of implant surfaces may serve to prevent bacterial colonization. The authors set out to develop an in vitro test system for the analysis of prevention of biofilm formation by Staphylococcus epidermidis and Staphylococcus aureus on implant materials. Biofilm growth was monitored over 10 days on titanium disks in order to develop appropriate test parameters. Bacterial cell counts following ultrasonic treatment of the colonized samples were compared with scanning electron microscope images of the specimens. Copper ion containing surfaces (ie copper [Cu] and inter-metallic Ti-Cu films) were used for growth inhibition assays: copper ion releasing specimens led to reduced bacterial numbers in biofilms and decreased bacterial persistence in the model used. The assay used represents an inexpensive and quick in vitro screen for the antibacterial effects of novel implant surface materials.

Evaluation of SV40-transformed synovial fibroblasts in the study of rheumatoid arthritis pathogenesis.

The SV40 T antigen has been used to generate immortalized cells from rheumatoid arthritis (RA) synovial fibroblasts (RASFs) that are commonly used in lieu of primary RASFs. In the current study, we investigated the effect of stimulation by tissue necrosis factor alpha (TNF-α) and interleukin 17 (IL-17) on primary and immortalized RASFs in order to gauge the appropriateness of the use of immortalized RASFs, the MH7A cell line, in the study of RA pathogenesis. Changes in the levels of secretion and expression of 8 proteins associated with RA upon stimulation were assessed by multiplex immunoassay. IL-17 stimulation had a minimal impact on protein secretion and expression for primary and immortalized cells. Basic fibroblast growth factor (FGF-2) was not detectable for the primary cells but was detectable for the immortalized cells. In contrast, monocyte chemoattractant protein 1 (MCP-1) was detectable for primary cells but was undetectable for immortalized cells. In general, protein expression and secretion by cells stimulated with TNF-α were significantly increased. For primary cells, several proteins were below the limit of detection for unstimulated cells and cells stimulated with IL-17, while levels for TNF-α-stimulated cells were within the detectable range. For the same proteins, expression was observed for immortalized cells, regardless of stimulation, suggestive of constitutive activation of the NF-κB signaling pathway. The current study therefore provides strong evidence that immortalized and primary RASFs differ in regard to protein expression and secretion and therefore may not be appropriate for use in the study of RA pathogenesis.

[Musculoskeletal modeling of the patellofemoral joint. Dynamic analysis of patellar tracking]. / Muskuloskelettale Modellierung des patellofemoralen Gelenks. Dynamische Analyse der patellaren Führung.

Numerical simulations contribute to the understanding of patellofemoral diseases. Whereas cadaveric studies are limited with respect to reproducibility of results, the impact of different operative approaches can be systematically evaluated based on mathematical models. The objective of this study was to introduce a musculoskeletal model which is capable of describing the dynamic interactions within the patellofemoral joint. It contains major bony and soft tissue structures of the right leg including the medial patellofemoral ligament (MPFL). Two operative approaches were considered based on the model to illustrate the effect on patellofemoral biomechanics during active knee flexion: On the one hand the effect of femoral insertion during MPFL reconstruction on medial soft tissue tension, and on the other hand the difference in patella kinematics before and after total knee arthroplasty. Finally, the potential of musculoskeletal models is discussed.

[Principles of tribological analysis of endoprostheses]. / Grundlagen zur tribologischen Analyse von Endoprothesen.

For the tribological characterization of artificial joints, various experimental methods are currently available. However, the in vitro test conditions applied are only comparable in a limited way and transferability to the in vivo situation is also restricted. This is due to the different wear simulation concepts used and partly insufficient simulation of clinical worst case situations. In the present paper current scientific methods and procedures for tribological testing of artificial joints are presented. In addition, the biological effects of wear products are described enabling clinicians to challenge tribological studies and to facilitate specific interpretation of scientific results taking the clinical situation into account.

Cancer-related knowledge, attitudes, and risk perception among 6 grade students in Jordan.

UNLABELLED: Elementary schools in Jordan have included health education material in curricula to promote healthy lifestyles among younger school children. However, the relation between healthy lifestyles and the prevention of chronic diseases such as cancer has not been an explicit component in school curricula of younger age groups. We sought to explore the level of knowledge among 6th grade students as well as their attitudes with respect to cancer. This comes as part of a pilot project to develop an educational series on cancer prevention that aims to meet knowledge gaps specific to the community of students in this age group in Jordan. METHODS: A questionnaire composed of items measuring knowledge about cancer and cancer prevention through healthy practices, attitudes towards cancer, and intentions to engage in healthy behaviors was developed. Questionnaires previously used in similar age groups elsewhere were used as a reference. Our questionnaire was reviewed and approved by the Ministry of Education - School Health & Nutrition Department. Sixth graders in a convenience sample of four schools selected by the Ministry of Education completed the self-administered questionnaire. RESULTS: Ninety-six 6th graders from four schools answered the baseline survey, but 28% of the surveys were excluded from the analysis (data quality problems) leaving 69 student participants. In the original sample of 96 students, 48 (69.6%) were girls. Among the 69 student participants, 67 (97.1%) had heard of cancer, but fewer than 44 (63.8% knew it was not a contagious disease. Regarding fear, 29 (42%) would not play with a cancer patient. Concerning prevention of the most prevalent cancers in Jordan as research has shown that certain risk factors increase the chance that a person will develop cancer. The most common risk factors are smoking, Poor diet, lack of physical activity, or being overweight, 25 (36.2%) knew breast cancer was preventable, and 28 (40.6%) and 24 (34.8%) knew this regarding lung and colorectal cancers, respectively. About 40 (57.8%) students identified healthy dietary behaviors (e.g., low fat, low sugar), but only six could identify the ideal frequency for exercise (60 minutes daily). Fifty-eight (84.1%) agreed that cigarettes harmed the health. However, only 21 (30.4%) found it easy to avoid exposure to secondhand smoke. Nine (13%) reported smoking water pipes, but only one reported smoking cigarettes. Forty-eight (69.6%) and 47 (68.1%) agreed that daily physical activity and healthy eating were important, respectively. Fifty-two (75.4%) students found it easy to eat healthy at home, but only 37 (53.6%) found it easy to do so at school. Finally, 63 (91.3%) students wanted to learn more about cancer. CONCLUSION: Although a significant number of our sample of students has heard about cancer and students exhibit some knowledge regarding healthy practices, our results show that knowledge gaps exist with regard to the nature of cancer as a noncontagious disease, the preventability of specific cancers, and the link between specific risk factors and cancer.

Subject specific finite element modelling of periprosthetic femoral fractures in different load cases.

Periprosthetic femoral fractures (PFF) around total hip replacements are one of the biggest challenges for orthopaedic surgeons. To understand the risk factors and formation of these fractures, the development of a reliable finite element (FE) model incorporating bone failure is essential. Due to the anisotropic and complex hierarchical structure of bone, the mechanical behaviour under large strains is difficult to predict. In this study, a state-of-the-art subject specific FE modelling technique for bone is utilised to generate and investigate PFF. A bilinear constitutive law is applied to bone tissue in subject specific FE models of five human femurs which are virtually implanted with a straight hip stem to numerically analyse PFF. The material parameters of the models are expressed as a function of bone ash density and mapped node wise to the FE mesh. In this way the subject specific, heterogeneous structure of bone is mimicked. For material mapping of the parameters, computed tomography (CT) images of the original fresh-frozen femurs are used. Periprosthetic fractures are generated by deleting elements on the basis of a critical plastic strain failure criterion. The models are analysed under physiological and clinically relevant conditions in two different load cases re-enacting stumbling and a sideways fall on the hip. The results of the analyses are quantified with experimental data from previous work. With regard to fracture pattern, stiffness and failure load the simulations of the load case stumbling delivered the most stable and accurate results. In general, mapping of material properties was found to be an appropriate way to reproduce PFF with finite element models.

Novel approach to estimate distraction forces in distraction osteogenesis and application in the human lower leg.

PURPOSE: In distraction osteogenesis (DO) of long bones, new bone tissue is distracted to lengthen limbs or reconstruct bone defects. However, mechanical boundary conditions in human application such as arising forces are mainly based on limited empirical data. Our aim was the numerical determination of the callus distraction force (CDF) and the total distraction force (TDF) during DO in the tibia of adults to advance the understanding of callus tissue behavior and optimize DO procedures. METHOD: We implemented a mathematical model based on an animal experiment to enable the calculation of forces arising while distracting callus tissue, excluding the influence of surrounding soft tissue (muscles, skin etc.). The CDF progression for the distraction period was calculated using the implemented model and varying distraction parameters (initial gap, area, step size, time interval, length). Further, we estimated the CDF based on reported forces in humans and compared the results to our model predictions. In addition, we calculated the TDF based on our CDF predictions in combination with reported resisting forces due to soft tissue presence in human cadavers. Finally, we compared the progressions to in vivo TDF measurements for validation. RESULTS: Due to relaxation, a peak and resting CDF is observable for each distraction step. Our biomechanical results show a non-linear degressive increase of the resting and peak CDF at the beginning and a steady non-linear increase thereafter. The calculated resting and peak CDF in the tibial metaphysis ranged from 0.00075 to 0.0089 N and 0.22-2.6 N at the beginning as well as 20-25 N and 70-75 N at the end of distraction. The comparison to in vivo data showed the plausibility of our predictions and resulted in a 10-33% and 10-23% share of resting CDF in the total resting force for bone transport and elongation, respectively. Further, the percentage of peak CDF in total peak force was found to be 29-58% and 27-55% for bone transport and elongation, respectively. Moreover, our TDF predictions were valid based on the comparison to in vivo forces and resulted in a degressive increase from 6 to 125 N for the peak TDF and from 5 to 76 N for the resting TDF. CONCLUSION: Our approach enables the estimation of forces arising due to the distraction of callus tissue in humans and results in plausible force progressions as well as absolute force values for the callus distraction force during DO. In combination with measurements of resisting forces due to the presence of soft tissue, the total distraction force in DO may also be evaluated. We thus propose the application of this method to approximate the behavior of mechanical callus properties during DO in humans as an alternative to in vivo measurements.