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Geant4 is a software toolkit for the simulation of the passage of particles through matter. It is used by a large number of experiments and projects in a variety of application domains, including high energy physics, astrophysics and space science, medical physics and radiation protection. Its functionality and modeling capabilities continue to be extended, while its performance is enhanced. An overview of recent developments in diverse areas of the toolkit is presented. These include performance optimization for complex setups; improvements for the propagation in fields; new options for event biasing; and additions and improvements in geometry, physics processes and interactive capabilities. Index Terms--Electromagnetic interactions, hadronic interactions, object-oriented technology, particle interactions, physics validation, simulation.

Background: The effects of immobilization on passive muscle mechanical properties are inconsistent between studies. Here, we investigated the mechanical properties of immobilized muscle by obtaining length-force curves within and beyond the physiological muscle-tendon length in a knee-contractured rat model., Methods: Unilateral rat knee joints were immobilized using an external fixator for up to 21 days. Length-passive force relationships in the immobilized and contralateral semitendinosus muscles were determined by tensile testing., Findings: The semitendinosus muscle-tendon length at end physiologic length in vivo was approximately at 5% strain of the slack length. Dynamic, elastic, and viscous force (three aspects of muscle mechanical properties) evoked by instantaneous constant stretch were higher than contralateral side within the physiological muscle-tendon length limit (strains of 5% or 5%-7.5% slack length). When beyond muscle-tendon length corresponding to the maximum knee extension (strains of 7.5% or 10%-20% slack length), there was no difference between the two sides. Dynamic and elastic stiffness were also larger, as estimated by tangent angles of length-force curves, at strains of 5% slack length, and matched contralateral levels at strains of 7.5% slack length on day 21. There were no differences in semitendinosus muscle-tendon lengths overtime. Despite significantly reductions in knee extension range of motion, collagen content only showed slight changes and correlation was hardly detected between collagen and mechanical properties on day 21., Interpretation: Viscoelasticity in immobilized semitendinosus muscle increased within the physiological muscle-tendon length. Collagen content may have little effect on passive force and stiffness., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Although anterior cruciate ligament reconstruction surgery is known to cause joint contracture, the mechanisms of this process are unknown. We aimed to assess the effects of transection of this ligament and each phase of reconstruction surgery on contracture formation., Materials and Methods: Rats were divided into groups according to treatment received: sham (arthrotomy), ligament transection, ligament transection plus bone drilling, and ligament reconstruction. Surgery was performed on the right knee. Untreated left knees in the sham group were used as controls., Results: At 7 and 28 d post-surgery, range of motion before myotomy, mainly representing myogenic contracture, was restricted in the sham and ligament transection groups, and more so in the bone drilling and reconstruction groups. Restricted range of motion after myotomy, representing arthrogenic contracture, was detected at both timepoints in the bone drilling and reconstruction groups, but not in the sham or ligament transection groups. At 3 d post-surgery, although a large blood clot was observed in all three treatment groups, only the bone drilling and reconstruction groups showed significant joint swelling. At 7 d post-surgery, inflammatory-cell infiltration into the joint capsule was most apparent in the bone drilling and reconstruction groups, and joint capsule fibrosis was also most apparent in these groups at 7 and 28 d post-surgery., Conclusions: Our results suggest that (1) myogenic contracture after anterior cruciate ligament reconstruction is caused by arthrotomy and aggravated by bone drilling, and (2) arthrogenic contracture is mostly due to bone drilling, which triggers an inflammation-fibrosis cascade.

Objective: The process of anterior cruciate ligament (ACL) injury-induced meniscal tear formation is not fully understood. Clinical studies have shown that ACL reconstruction (ACLR) reduces the development of secondary meniscal tears, but it is difficult to gain insight into the protective effects of ACLR from clinical studies alone. Using rat ACL transection (ACLT) and ACLR models, we aimed to reveal (1) the formation process of meniscal tears secondary to ACLT and (2) the protective effects of ACLR on secondary meniscal tears., Design: ACLT surgery alone or with ACLR was performed on the knees of rats. Histomorphological and histopathological changes were examined in the posteromedial region of the meniscus in intact rats and in rats that received ACLT or ACLR up to 12 weeks postsurgery. In addition, anterior-posterior joint laxity was measured using the universal testing machine to evaluate the effects of ACLT and ACLR on joint laxity., Results: AAnterior-posterior laxity was significantly increased by ACLT compared to the intact knee. This ACLT-induced joint laxity was partially but significantly reduced by ACLR. Meniscal proliferation and hyaline cartilage-like tissue formation were detected in the medial meniscus at 4 weeks post-ACLT. At 12 weeks post-ACLT, hyaline cartilage-like tissue was replaced by ossicles and meniscal tears were observed. These ACLT-induced abnormalities were attenuated by ACLR., Conclusions: Our results suggest that ACLT-induced joint laxity induces secondary medial meniscal tears through meniscal proliferation and ossicle formation via endochondral ossification. Joint re-stabilization by ACLR suppresses meniscal proliferation and ossicle formation and consequently prevents secondary meniscal tears.

Background: To elucidate the formation process and therapeutic targets of hip flexion contracture, we developed a rat model of hip flexion contracture induced by hip mono-articular immobilization., Methods: Kirschner wires inserted into the femur and hip bone were anchored at the hip in a flexed position in the immobilization groups and unanchored in the sham groups for up to four weeks. Age-matched untreated rats were used as controls. Hip extension range of motion (RoM) was measured at three different extension moments (7.5, 15, and 22.5 N•mm) in each successive myotomy step as follows: before myotomy, after sequential myotomy of the tensor fascia lata, quadriceps muscle, iliopsoas muscle, and after myotomy of all residual muscles (the gluteus medius and adductor muscles). Histological analysis of the hip joint was also performed., Findings: After four weeks of immobilization, the RoM before myotomy at 22.5 N•mm was significantly decreased by 29° compared with controls, and this value was unaltered in the sham group. Analyses following serial myotomy suggested that the structures responsible for myogenic contracture were the tensor fascia lata, iliopsoas, gluteus medius, and adductor muscles because the RoMs were increased by these myotomies. Unexpectedly, arthrogenic contracture was not detected at moments other than at 7.5 N•mm, even after four weeks of immobilization. Histological analysis confirmed that pathological changes were not apparent in the anterior capsule of the hip joint., Interpretation: The present findings suggest that myogenic contracture may be an important therapeutic target for immobilization-induced hip flexion contracture., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose : Complications including arthrofibrosis have been reported after anterior cruciate ligament reconstruction (ACLR) even under accelerated rehabilitation. To overcome this, we developed an animal model of ACLR-induced arthrofibrosis without immobilization. Materials and Methods : Thirteen male Wistar rats were divided into ACL transection (ACLT) and ACLR groups. Surgery was performed in the right knees and untreated left knees were used as controls. After surgery, rats could move freely without joint immobilization. Results : One week after surgery, flexion contracture represented by passive ROM reduction was 49 ± 5° and 21 ± 6° in ACLR and ACLT groups, respectively. Thereafter, flexion contractures were gradually reduced to 21 ± 8° and 12 ± 6° after 12 weeks, respectively. Fibrosis, which is characterized by significant upregulation of fibrosis-related genes, thickening, and adhesion in the posterior joint capsule, was observed in the ACLR group after 12 weeks of surgery. Nociceptive behavior and joint swelling were more apparent in the ACLR group than in the ACLT group, especially after 1 week of surgery. Discussions : We developed a rat model of ACLR-induced joint contracture due to arthrofibrosis without rigid immobilization. Joint contracture was also observed in the ACLT group, but to a considerably milder degree than in the ACLR group. Thus, signs of inflammation as a result of reconstruction surgery, rather than ACL transection, play an important role in the formation of joint contracture after ACLR. Our animal model is suited to examine the mechanisms and efficacy of therapeutic strategies for arthrofibrosis following ACLR treated without rigid joint immobilization.

Knee joint contracture is often induced by anterior cruciate ligament reconstruction (ACLR). However, the temporal and spatial arthrofibrotic changes following inflammatory events, which occur in parallel with the formation of joint contractures after ACLR, are unknown. This study aimed to reveal: (a) time-dependent changes in myogenic and arthrogenic contractures; and (b) the process of arthrofibrosis development after ACLR. ACLR was performed on knees of rats unilaterally. Passive ranges of motions (ROMs) before and after myotomy, as well as inflammatory and fibrotic reactions, were examined before and after the surgery at various periods up to 56 days. Both ROMs before and after myotomy exhibited their lowest value on day 7 and increased thereafter in a time-dependent manner; nevertheless, significant restrictions remained by day 56. Myotomy partially increased ROMs at all time points, indicating contribution of the myogenic component to ACLR-induced contracture. Inflammatory and fibrotic reactions peaked on day 7. Arthrofibrosis, characterized by the thickening of the joint capsule and the shortening of the synovial length, was established by day 7 and was not completely resolved by day 56. Our results indicate that: (a) both myogenic and arthrogenic contractures generated through ACLR develop maximally by day 7 after surgery and subside thereafter, but persist at least until day 56; and (b) arthrofibrosis is established by day 7 after surgery and is not completely resolved by day 56. These findings suggest that treatment and intervention for preventing joint contracture after ACLR should be performed within the first 7 days after surgery., (© 2020 Orthopaedic Research Society. Published by Wiley Periodicals LLC.)

Background: Range of motion restriction following immobilization is spontaneously recovered at least in part by remobilization. However, the mechanisms underlying how muscles change with range of motion recovery are poorly understood. This study aimed to reveal morphological and biomechanical changes in the knee flexor semitendinosus muscle that contribute to knee joint contracture following the relief of immobilization., Methods: To induce flexion contracture, we immobilized rat right knees by an external fixator at a flexed position for three weeks. After removal of the fixator, the joints were allowed to move freely (remobilization) for up to 14 days. We obtained muscle length and passive stiffness of the isolated semitendinosus muscles after measuring passive knee extension range of motion., Findings: Three weeks of immobilization induced range of motion reduction, as well as changes in morphological and biomechanical properties of the semitendinosus muscle, such as reduced muscle length and increment of passive stiffness leading to myogenic contracture. Joint immobilization-induced reduction of range of motion, representing flexion contracture, was partially reduced by 14 days of remobilization. Concomitantly, both muscle length and muscle stiffness returned to levels not significantly different from those in the contralateral side during this period., Interpretation: These results suggest that improvement of myogenic contracture during the early phase of remobilization occurs via both morphological and biomechanical adaptations., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Although knee immobilization may deteriorate the mechanical parameters of the anterior cruciate ligament, such as stiffness and failure strength, it is unknown whether it induces laxity in the whole joint. We examined the effects of immobilization on anterior-posterior joint laxity and mechanical properties of the anterior cruciate ligament, as well as histological and gene expression profiles of the joint capsule in rat knee joints., Methods: Unilateral rat knees were immobilized using an external fixator. Non-immobilized contralateral knees were used as controls. After 3 weeks, anterior-posterior laxity in the whole joint (i.e., a complex of bones, ligaments, and capsule) and stiffness and failure strength in the anterior cruciate ligament were examined using a universal testing machine. Moreover, the knee joint capsule was histologically analyzed, and the expression levels of genes related to collagen turnover in the posterior joint capsule were examined., Findings: Joint immobilization slightly but significantly increased anterior-posterior laxity compared with the contralateral side. Unexpectedly, the stiffness and failure strength of the anterior cruciate ligament were not altered by immobilization. There was no correlation found between anterior cruciate ligament stiffness and anterior-posterior joint laxity. In the posterior joint capsule, thinning of the collagen fiber bundles accompanied by a decrease in COL3A1 gene expression was observed after immobilization., Interpretation: These results suggest that 3 weeks of joint immobilization alters the biomechanical integrity in the knee joint without altering the mechanical properties of the anterior cruciate ligament. Changes in the joint capsule may contribute to the immobilization-induced increase in anterior-posterior laxity., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Shortly after joint remobilization, inflammation is induced in the joint and aggravates joint contracture via subsequent fibrosis. However, the mechanisms involved in remobilization-induced inflammation are not yet fully understood. We hypothesized that joint immobilization followed by remobilization induces hypoxia/reoxygenation, initiating inflammatory reactions through nitric oxide (NO) production via NO synthase 2 (NOS2). This study aimed to investigate whether: 1) administration of the NOS inhibitor L-NG-nitroarginine methyl ester (l-NAME) can attenuate remobilization-induced joint inflammation; and 2) hypoxia/reoxygenation is induced by joint immobilization and followed by remobilization. Unilateral knee joints of rats were immobilized using external fixators for three weeks. After removal of the fixation device, knees were allowed to move freely for one day (remobilization) with or without l-NAME administration. Without l-NAME administration, inflammatory reactions including joint swelling and inflammatory cell infiltration, edema, and upregulation of inflammatory mediator genes in the joint capsule were detected following upregulation of the NOS2 gene after remobilization. These remobilization-induced inflammatory reactions were partially attenuated by administration of l-NAME. Therefore, NOS2/NO elevation has potential as a novel treatment for remobilization-induced joint inflammation. Gene expression of the hypoxia marker hypoxia inducible factor-1α was upregulated after one day of remobilization, rather than after immobilization. These results suggest that upregulation of NOS2 by remobilization might be not due to hypoxia/reoxygenation., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2020 Elsevier Inc. All rights reserved.)

We investigated whether the combination of exercise and anti-inflammatory/anti-fibrotic treatment using low-level laser therapy (LLLT) promotes recovery from joint contracture without arthrogenic contracture progression. Rat knees were immobilized for 3 weeks in a flexed position. After fixator removal, rats were divided into no intervention (RM), daily treadmill walking (WALK), and daily treadmill walking and LLLT (W + L) groups. Total and arthrogenic contractures were assessed by restrictions of passive range of motion (ROM) before (m-ROM) and after myotomy (a-ROM), respectively. After 7 days of remobilization, m-ROM restriction decreased equally in all groups. Conversely, a-ROM restriction further increased after remobilization in the RM and WALK groups. Furthermore, this restriction was significantly larger in the WALK group compared with the RM group. In the W + L group, however, progression of a-ROM restriction during remobilization was prevented. After 1 or 7 days of remobilization, inflammatory and fibrotic reactions in the joint capsule were induced in the RM group and were more pronounced in the WALK group, but these reactions were milder in the W + L group than in the WALK group. m-ROM restriction representing total contracture initially established by immobilization was partially improved by remobilization. Additional LLLT and exercise intervention did not further reduce total contracture, but LLLT suppressed the progression of arthrogenic contracture caused by ambulation and treadmill exercise. Therefore, exercise with LLLT in the early phase of remobilization would be one possible adjunct therapy to prevent further progression of arthrogenic contracture.

Joint mobility decreases in the elderly and in diabetics, this process is thought to be caused by accumulation of advanced-glycation end products (AGEs). Here, we aimed to elucidate the role of AGEs in joint contracture formation in rat knees. Rats were injected with ribose or saline into the knees twice weekly for 8 weeks. Pentosidine (AGE) levels were measured in the knee-joint tissues. After serial injections, rats were subjected to unilateral knee-joint immobilization in a flexion position for various periods. At day 21, the passive knee ranges of motions (ROMs) were measured. Knee joint histopathology were assessed, and the expression of fibrotic genes in the posterior joint capsules was examined using real-time PCR. Ribose injection induced a 7.0-fold increase in pentosidine levels relative to saline injection. Joint immobilization resulted in equal myogenic ROM restriction in both groups. Arthrogenic ROM restriction was greater with ribose injection in the immobilized joints (p < 0.05), but was not affected in nonimmobilized joints. Type-I (COL1A1) and type-III (COL3A1) collagen gene expression increased significantly in immobilized joints relative to nonimmobilized joints in the ribose group, but was not affected in the saline group. Ribose injection increased COL1A1 expression slightly and COL3A1 expression significantly in immobilized joints. Histologically, inflammatory changes appeared at day 3 of immobilization and peaked at day 7. These responses trended to be more severe and prolonged in the ribose group than in the saline group. Our data provide evidence for a causal relationship between AGEs and joint contracture formation following immobilization. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:854-863, 2018., (© 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

This study investigated the effects of treadmill walking during remobilization on range of motion (ROM) and histopathology in rat knee joints, which were immobilized for 3 wk in a flexed position. After fixator removal, rats were divided into a no-intervention (RM) group and a group forced to walk on a treadmill daily at 12 m/min for 60 min (WALK group). Passive knee extension ROMs were measured before (m-ROM) and after (a-ROM) knee flexor myotomy on the first and last day of a 7-day remobilization period, with m-ROM mainly reflecting myogenic factors and a-ROM reflecting arthrogenic factors. Knee joints were histologically analyzed and gene expression of inflammatory or fibrosis-related mediators in the posterior joint capsule were examined. m-ROM and a-ROM restrictions were established after immobilization. m-ROM significantly increased following the remobilization period both in RM and WALK groups compared with that of immobilized (IM) group. Conversely, a-ROM decreased following the remobilization period in both RM and WALK groups compared with that of IM group. Importantly, a-ROM was smaller in the WALK group than the RM group. Remobilization without intervention induced inflammatory and fibrotic reactions in the posterior joint capsule after 1 and 7 days. Treadmill walking promoted these reactions and also increased the expression of fibrosis-related TGF-β1 and collagen type I and III genes. While free movement after immobilization improved myogenic contracture, arthrogenic contracture worsened. Treadmill walking further aggravated arthrogenic contracture through amplified inflammatory and fibrotic reactions. Thus active exercise immediately after immobilization may not improve immobilization-induced joint contracture. NEW & NOTEWORTHY In clinical practice, it is widely accepted that facilitation of joint movements is effective in improving immobilization-induced joint contracture. However, whether active exercises improve arthrogenic contracture is not known. In this study, we revealed that treadmill walking further promoted remobilization-induced progression of arthrogenic contracture. To our knowledge, this is the first study demonstrating no favorable effect of active exercise on immobilization-induced arthrogenic contracture.