Effect of Changing the Joint Kinematics of Knees With a Ruptured Anterior Cruciate Ligament on the Molecular Biological Responses and Spontaneous Healing in a Rat Model

Kokubun, Takanori; Kanemura, Naohiko; Murata, Kenji; Moriyama, Hideki; Morita, Sadao; Jinno, Tetsuya; Ihara, Hidetoshi; Takayanagi, Kunio

doi:10.1177/0363546516654687

Cited by 25 publications

(35 citation statements)

References 46 publications

(61 reference statements)

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“…A recent study established a relationship between the spontaneous healing response and abnormal tibiofemoral subluxation by designing an ACL spontaneous healing rodent model. In this model, abnormal tibiofemoral subluxation following surgically transected ACL was prevented by using nylon structures at the extra-articular capsule (Figures 2 and 3) [41]. The authors demonstrated spontaneous healing of the ACL in this model, and observed that the gap between the tibial and femoral remnants of the ligament was bridged by tissue that consisted of important extra-cellular matrix components including collagen type I and III.…”

Section: Novel Candidate For Acl Healingmentioning

confidence: 85%

“…A better understanding of the reasons for the failure of ACL to spontaneously heal will help us develop newer treatment methods. Although we are still unaware of the entire mechanism, and the signaling pathways involved in ACL spontaneous healing, recent studies have identified few probable candidates that may be possible key players [41,[47][48][49][50]. Some studies have reported that injured ACL has the same functional healing response as other extra-articular ligaments in terms of cellularity and vascularity.…”

Section: Discussionmentioning

confidence: 99%

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Key Determinants of Anterior Cruciate Ligament Spontaneous Healing

Kokubun¹,

Kanemura²,

Murata³

et al. 2017

J Osteopor Phys Act

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Anterior cruciate ligament (ACL) injuries are known to have very low rates of spontaneous healing. There have been several studies since the mid-1960s concerning the approaches to accelerate spontaneous healing of ACL injuries. Recent studies have identified similarities in the healing response of ACL and other extra-articular ligaments, in terms of their cellular response and vascularity. Research has demonstrated that mechanical stress has an important influence on the biological response of tissue healing. Novel treatment approaches may exploit the role of mechanical loads on the regulation of gene expression in achieving spontaneous healing of injured ACL. This article reviews the determinants of the ACL healing response and their relationship to mechanical stress and spontaneous healing, and explores novel concepts that are emerging in the management of ACL injuries. Keywords Current Treatment for ACL injuriesThe anterior cruciate ligament (ACL) plays an important role in motion at the knee joint and therefore, in the related physical activities of daily living. The ACL stabilizes the knee and guides the movement of the tibia and femur at the joint. Injuries involving the ACL are well known for hopeless of spontaneous healing. Several studies have investigated the mechanisms of low healing response and the approaches to accelerating spontaneous healing of ACL injuries, since the mid-1960s [1][2][3][4]. The reasons for the failure of the ACL to heal spontaneously are related to specific intra-articular features [5,6] as well as owing to various molecular biological characteristics [7,8]. A number of studies have addressed on explaining the reasons for the failure of the ACL to heal spontaneously [1,3,[9][10][11][12][13]. Since ACL injuries contribute to an increased risk of knee osteoarthritis [14,15], the current gold standard for the management of complete ACL rupture is reconstruction using a tendon autograft. However, there are no highquality randomized controlled trials comparing ACL reconstruction with other modalities of treatment [16][17][18][19].However, it is clear that the spontaneous healing capacity of the ACL has been underestimated. Several clinical studies have reported results of ACL healing with non-surgical treatment alone [20][21][22]. Moreover, an organ culture model of the human ACL showed a high intrinsic healing capacity [23]. Although these studies have demonstrated that the human ACL remnant has functional healing capacities, this was not proved in rigorous scientific methods. Consequently, current non-surgical treatment for ACL injuries aims at rehabilitating patients to modify the patients' physical activities to continue their dairy living, but not to support their spontaneous healing of the injured ACL [24,25]. This comprises muscle strength exercises, range of motion exercises, neuro-muscular training, and bracing. To summarize, although surgical reconstruction with autograft is considered to be the standard of care for restoring knee function following complete ACL in...

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Section: Novel Candidate For Acl Healingmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Key Determinants of Anterior Cruciate Ligament Spontaneous Healing

Kokubun¹,

Kanemura²,

Murata³

et al. 2017

J Osteopor Phys Act

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“…Prior research showed that changing the joint kinematics of a knee with complete ruptured ACL results in the down-regulation of inflammatory responses [ 33 ] and leads to spontaneous healing [ 27 ]. These previous studies used the CAM model used for the purpose of controlling abnormal knee joint movement without restricted knee flexion (Fig.…”

Section: Methodsmentioning

confidence: 99%

“…Then, the skin was closed only in the ACL-T group. In the CAM group, a 2–0 nylon suture (Prolene, Ethicon Endo-Surgery Japan) was passed through the tibial bone tunnel posterior to the condyle of the distal end of the femur and was then tied to the joint in order to prevent abnormal tibial translation, according to the same procedure as that used in previous study [ 27 ]. The nylon suture provided a directed traction force to resist the anterior motion of the tibia without restricted knee flexion (Fig.…”

Section: Methodsmentioning

confidence: 99%

“…A previous study demonstrated the effects of controlled abnormal joint motion on modifying the intra-articular molecular response of ACL-ruptured knees, which led to spontaneous ACL healing [ 27 ]. Although that study demonstrated a new mechanism of ACL healing, the molecular biological responses of the intra-articular tissues during the ACL healing process in the acute phase of injury remain unclear.…”

Section: Introductionmentioning

confidence: 99%

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Effects of controlled abnormal joint movement on the molecular biological response in intra-articular tissues during the acute phase of anterior cruciate ligament injury in a rat model

Nishikawa

Kokubun

Kanemura

et al. 2018

BMC Musculoskelet Disord

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BackgroundThe anterior cruciate ligament (ACL) is responsible for braking forward movement of the tibia relative to the femur and for tibial rotation. After ACL injury, this braking performance deteriorates, inducing abnormal joint movement. The purpose of this study was to clarify the effects of controlled abnormal joint movement on the molecular biological response in intra-articular tissues during the acute phase of ACL injury.MethodsEighty-four mature Wistar male rats were randomly assigned to a controlled abnormal movement (CAM) group, an ACL-transection (ACL-T) group, a sham-operated group, or an intact group. The ACL was completely transected at its midportion in the ACL-T and CAM groups, and a nylon suture was used to control abnormal tibial translation in the CAM group. The sham-operated group underwent skin and joint capsule incisions and tibial drilling without ACL transection. Animals were not restricted activity until sacrifice 1, 3, or 5 days after surgery for histological and gene expression assessments. Acute-phase inflammation requires an important balance between degenerative and biosynthetic processes and is controlled by the activities of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). Both types of gene were analyzed in this study.ResultsThe ACL-T and CAM groups exhibited cleavage of the ACL at all time points. However, for the CAM group, the gap in the ligament stump was extremely small, and fibroblast proliferation was observed around the stump. Relative to the ACL-T group, the CAM group demonstrated significantly lower expression of MMP-13 mRNA and a lower MMP-13/TIMP-1 ratio on days 1 and 5 in the ACL, the medial meniscus and the lateral meniscus. The expression of TIMP-1 mRNA was not significantly different between the ACL-T and CAM groups.ConclusionsThe study results suggested that controlling abnormal movement inhibited the inflammatory reaction in intra-articular tissues after ACL injury. This reaction was down-regulated in intra-articular tissues in the CAM group. Abnormal joint control caused prolonged inflammation and inhibited remodeling during the acute phase of ACL rupture.

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Preclinical tendon and ligament models: Beyond the 3Rs (replacement, reduction, and refinement) to 5W1H (why, who, what, where, when, how)

Little

Amadio

Awad

et al. 2023

Journal Orthopaedic Research

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Several tendon and ligament animal models were presented at the 2022 Orthopaedic Research Society Tendon Section Conference held at the University of Pennsylvania, May 5‐7, 2022. A key objective of the breakout sessions at this meeting was to develop guidelines for the field, including for preclinical tendon and ligament animal models. This review summarizes the perspectives of experts for eight surgical small and large animal models of rotator cuff tear, flexor tendon transection, anterior cruciate ligament tear, and Achilles tendon injury using the framework: “Why, Who, What, Where, When, and How” (5W1H). A notable conclusion is that the perfect tendon model does not exist; there is no single gold standard animal model that represents the totality of tendon and ligament disease. Each model has advantages and disadvantages and should be carefully considered in light of the specific research question. There are also circumstances when an animal model is not the best approach. The wide variety of tendon and ligament pathologies necessitates choices between small and large animal models, different anatomic sites, and a range of factors associated with each model during the planning phase. Attendees agreed on some guiding principles including: providing clear justification for the model selected, providing animal model details at publication, encouraging sharing of protocols and expertise, improving training of research personnel, and considering greater collaboration with veterinarians. A clear path for translating from animal models to clinical practice was also considered as a critical next step for accelerating progress in the tendon and ligament field.This article is protected by copyright. All rights reserved.

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Effect of Changing the Joint Kinematics of Knees With a Ruptured Anterior Cruciate Ligament on the Molecular Biological Responses and Spontaneous Healing in a Rat Model

Abstract: Elucidating the relationship between the mechanotransduction mechanism and healing responses in knees with completely ruptured ACLs may result in the development of novel nonsurgical treatment that enables the ACL to spontaneously heal in patients who are not suitable for reconstruction.

Cited by 25 publications

References 46 publications

Key Determinants of Anterior Cruciate Ligament Spontaneous Healing

Key Determinants of Anterior Cruciate Ligament Spontaneous Healing

Effects of controlled abnormal joint movement on the molecular biological response in intra-articular tissues during the acute phase of anterior cruciate ligament injury in a rat model

Preclinical tendon and ligament models: Beyond the 3Rs (replacement, reduction, and refinement) to 5W1H (why, who, what, where, when, how)

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