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REVIEW ARTICLE

Clinics in Shoulder and Elbow

Clinics in Shoulder and Elbow Vol. 18, No. 1, March, 2015 http://dx.doi.org/10.5397/cise.2015.18.1.52

Characteristics of Animal Shoulder Models for Rotator Cuff Experiments Min-Cheol Kim and Myung-Sun Kim Department of Orthopaedic Surgery, Chonnam National University Medical School, Gwangju, Korea

Animal shoulder models are important in the investigation of the natural history of various pathologic conditions and for evaluation of the effectiveness of different treatments and biomaterials. The characteristics of animal shoulder models that may be used for rotator cuff related experiments are different with regard to the anatomy, behavioral pattern, advantages and disadvantages in application to each other. The lower primates and all the non-primate species, except the tree kangaroo, were neither functional overhead nor had a true rotator cuff. Utilizing more advanced primates, or perhaps even the tree kangaroo would be ideal and the most relevant to man as they possess a true rotator cuff. However, ethical concerns, costs, and many limitations in obtaining primates generally preclude the use of these animals for such research. Finally we should consider the differences in comparative anatomy and behavioral pattern of each animal model during performance or interpretation of rotator cuff experiments. (Clin Shoulder Elbow 2015;18(1):52-58) Key Words: Rotator cuff; Animal shoulder model; Anatomical characteristics

Introduction Despite improvements in understanding of the disease process of rotator cuff (RC) tear and advances in surgical techniques and instruments, retear after RC repair remains a significant clinical issue. The reported rates of unsuccessful repair range from 20% to 70%,1-3) depending on patient age, tear size and chronicity, muscle atrophy and degeneration, tendon quality, repair technique, and postoperative rehabilitation. Therefore, various animal studies have investigated the pathogenesis of RC disease and attempted to develop strategies to increase the tendon healing of large, chronic RC tears.4-6) With regard to the animal study, subcutaneous7-9) and abdominal wall10-16) sites of mice, rats, rabbits, and dogs have been common implant locations for screening the host response to a variety of biomaterials intended for human implantation. However, in tendon- and ligament-to-bone repair, mechanical loading17-19) and the presence of joint synovial fluid20,21) are known to

profoundly influence the form and function of the repair tissue. Therefore, it may be reasonable to assume that the orthotopic animal shoulder model is more appropriate for investigation of a variety of biomaterials intended for human RC tendon repair and the pathogenesis of RC disease. Animal shoulder models are important in the investigation of the natural history of various pathologic conditions and for evaluation of the effectiveness of different treatments and biomaterials. However, the characteristics of animal shoulder models that may be used for RC related experiments are different with regard to the anatomy, behavioral pattern, advantages, and disadvantages in application to each other. In addition, the most important distinguishing characteristic of human RC is that it is a true RC. A true RC is distinguished by the blending of individual flat tendons to form a common insertion. While most collagen fibers still run longitudinally in this setting, orthogonally aligned transverse fibers serve to hold the tendons together. Contractions of individual muscles can then exert

Received July 29, 2014. Revised November 19, 2014. Accepted November 30, 2014. Correspondence to: Myung-Sun Kim Department of Orthopaedic Surgery, Chonnam National University Medical School, 42 Jebong-ro, Dong-gu, Gwangju 501-757, Korea Tel: +82-62-227-1640, Fax: +82-62-225-7794, E-mail: [email protected] Financial support: None. Conflict of interests: None. Copyright © 2015 Korean Shoulder and Elbow Society. All Rights Reserved. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

pISSN 2383-8337 eISSN 2288-8721

Characteristics of Animal Shoulder Models for Rotator Cuff Experiments Min-Cheol Kim and Myung-Sun Kim

a pull through their own and also through neighboring tendons. This arrangement facilitates force transmission across the RC, allowing more effective and efficient function of the shoulder. The purpose of this review is to summarize the characteristics of animal shoulder models for RC experiments with regard to the anatomy, behavioral pattern, advantages and disadvantages.

Rat (Rodents) Shoulder Model Anatomical Characteristics The rat has an enclosed arch created by the acromion, coracoid, and clavicle, through which the supraspinatus (SSP) tendon passes repetitively during shoulder motion.22) The portion of the rat SSP muscle that passes under the acromial arch is muscular, and not tendinous, as it is in the human. In a rat, the SSP tendon is shorter than the infraspinatus (ISP) tendon (Fig. 1).23) The SSP tendon is longer than the SSP tendon in a human. There was increased fatty infiltration in the ISP, which may be due in part to the anatomic differences of the muscle. ISP muscle may better represent the findings seen in the human SSP tendon as it undergoes more fatty infiltration and more retraction of the muscle.

Advantages and Disadvantages The rat model has some advantages. Cost and ethical burden can be decreased due to use of small animals. Rat shoulder model is the appropriate animal model for studying a wide range of RC pathologies because defects made to the rat RC result in inferior biomechanical and other properties. Regarding disadvantages of the rat model, rats possess much better regeneration potency in their musculoskeletal system than humans. First, pathophysiology in muscle atrophy and fat

SSP ISP TM

Fig. 1. Photographs show individual tendons of supraspinatus (SSP), infraspinatus (ISP) and teres minor (TM), i.e. not forming a true rotator cuff in the rat. Cited from the article of Sonnabend and Young (J Bone Joint Surg Br. 2009;91:1632-7) with original copyright holder’s permission.23)

infiltration in rats may differ from that in humans.24) The transection of rat SSP tendon demonstrated spontaneous healing of the tendon. Muscle mass was regained after tendon healing and no fat infiltration was observed. Second, the rat shoulder is small in size, making surgical procedures tedious and tissues delicate to handle. Third, the rat is a quadruped, and although it uses its arms for reaching and grasping, it also uses them for locomotion. It could be argued that this makes the shoulders ‘weight bearing’ in some circumstances, unlike the human. Fourth, rat model does not reflect the degenerative, age-related large RC tears commonly seen in humans, who tend to present with intrinsic degenerative changes in the torn RC tendon (tendinosis), tendon retraction, and osteoporosis of the greater tuberosity.25) As the RC tendon-to-bone healing process may be 2 or 3 times faster in rats than humans, our 2- and 6-week immobilization corresponds to 4 to 6 weeks and 12 to 18 weeks in humans, respectively.26)

Rabbit (Lagomorpha) Shoulder Model Anatomical Characteristics With regard to the bony anatomy of the rabbit scapula, the acromion is a relatively rudimentary structure. The most unique attribute of the rabbit scapula is an additional bony prominence, or tunnel, on the anterior aspect of the glenohumeral joint (Fig. 2).27)

Advantages and Disadvantages The rabbit is larger than the more widely used rat, which affords an opportunity for more precise and consistent surgical procedures. The rabbit’s shoulder motion is similar to that of human when the SSP tendon moves under the acromion during elevation and abduction of the humerus. Also, subscapularis functions in the rabbit are similar to those of the human SSP. The rabbit subscapularis tendon traveling in its bony tunnel is the only model that is analogous to the human anatomy. Rabbit subscapular nerve is tethered to the adjacent osseous architecture and thus it is possible that a neuronal injury, in the setting of retraction of the myotendinous unit, occurs by a similar mechanism in both humans and rabbits. It provides the irreparable structural and functional changes of the musculotendinous unit associated with chronic RC tear by experimental SSP tendon release in the rabbit.28) The rabbit RC model is well accepted for investigation of pathologic conditions of muscle because it reproduces the key structural findings for muscle deterioration seen in humans and sheep after detachment of its tendon (Fig. 3).27) However rabbit is a quadraped with a weight-bearing glenohumeral joint. This characteristic may change the histological and mechanical response of the shoulder to injury, given a larger joint reactive force experienced with weight bearing.

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A

B

C

D

Fig. 2. Photographs show anatomy of rabbit and human in the sagittal view. Computergenerated (A) and gross-anatomy (B) images of the glenoid and scapula of a rabbit and a human (C, D), illustrating the similarity of the rabbit subscapularis tendon (passing under the lesser tuberosity) to the human supraspinatus tendon. Cited from the article of Rowshan et al. (J Bone Joint Surg Am. 2010;92:2270-8) with original copyright holder’s permission.27)

Coracobrachialis

Subscapularis

A

B

C

Fig. 3. Gross-anatomy photographs of the rabbit scapula show the subscapularis fossa (A), the glenoid (B), and the muscle anatomy (C). The images demonstrate the osseous tunnel of the subscapularis tendon. Cited from the article of Rowshan et al. (J Bone Joint Surg Am. 2010;92:2270-8) with original copyright holder’s permission.27)

Dog (Canine) Shoulder Model Anatomical Characteristics Anatomy of the canine shoulder is similar to that of sheep and the ISP tendon is often used in research. Glenoid labrum of dogs has characteristics of enlarging and deepening the glenoid cavity. In the caudolateral area as a thin and compact seam, which is closely connected to the glenoid (Fig. 4).23)

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Advantages and Disadvantages Produce loads to the RC are comparable in magnitude to those experienced by the human during daily activities. And it is the animal model most often used to investigate the effect of various biological materials for the augmentation of RC repair.29-33)

Characteristics of Animal Shoulder Models for Rotator Cuff Experiments Min-Cheol Kim and Myung-Sun Kim

SSP SSP ISP ISP TM

TM

Fig. 4. Photographs show individual tendons of supraspinatus (SSP), infraspinatus (ISP) and teres minor (TM), i.e. not forming a true rotator cuff in the dog. Cited from the article of Sonnabend and Young (J Bone Joint Surg Br. 2009;91:1632-7) with original copyright holder’s permission.23)

TM ISP

SSP SSP ISP

TM

Fig. 5. Photographs show individual tendons of supraspinatus (SSP), infraspinatus (ISP) and teres minor (TM), i.e. not forming a true rotator cuff in the sheep. Cited from the article of Sonnabend and Young (J Bone Joint Surg Br. 2009;91:1632-7) with original copyright holder’s permission.23)

Sheep (Ovine) Shoulder Model Anatomical Characteristics The forelimb of sheep is weight bearing. There is no clavicle, no coracoacromial arch. The sheep has less-developed acromion (Fig. 5).23)

Advantages and Disadvantages The advantages of the sheep model are easiness to handle and housing, low animal cost and better acceptance to society for use in research. The ISP tendon is used in the ovine model because its size and function are similar to the human SSP tendon. Sheep ISP tendon has similar geometry and mechanical properties to those of the human SSP tendon, which serves as a good approximation of the human anatomy. Also, atrophy and

Fig. 6. Photographs show the true rotator cuff of the tree kangaroo with blending of the tendons of supraspinatus (SSP), infraspinatus (ISP) and teres minor (TM) on the dorsal and articular surface. Cited from the article of Sonnabend and Young (J Bone Joint Surg Br. 2009;91:1632-7) with original copyright holder’s permission.23)

fat infiltration in RC muscles after chronic RC tear in a sheep model are similar to those of human. Chronic injury ISP model in sheep, fat accumulation of 6.2% was noted at 18 weeks after injury. Acute, cyclic loads encountered in this model during convalescence are significantly greater than those in humans. Scar tissue forms between the detached tendon edges and the insertion site, which is common among all animal models, but does not occur in humans. This scar tissue could account for the apparent improved kinetics seen in the group with no tendon repair.

Kangaroo (Marsupials) Shoulder Model Regarding the anatomical characteristics of tree kangaroos, they have a fully-formed RC with the relevant tendons fusing well before their attachment to the greater tuberosity. Tree kangaroo can reach overhead and scratch the back of its head with its upper limb. It would be the ideal model and the most relevant to man as they possess a true RC (Fig. 6).23) www.cisejournal.org

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ISP

SSP SSP

ISP

A

TM

B

Fig. 7. Photographs of the rudimentary rotator cuff of the spider monkey show limited blending between the tendons of supraspinatus (SSP) and infraspinatus (ISP) on (A) the dorsal (teres minor, TM) and (B) the articular surface (the drill bit points to the fusion between SSP and ISP). Cited from the article of Sonnabend and Young (J Bone Joint Surg Br. 2009;91:1632-7) with original copyright holder’s permission.23)

SSP TM ISP TM SSP ISP

A

Primate Shoulder Model Anatomical Characteristics The anatomical characteristics of spider monkey are more definite, but still very limited; interconnection was found between the tendons of the spinati, but the tendon of teres minor (TM) did not appear to take part in this ‘cuff’. Spider monkey can raise its upper limb beyond 150° of forward flexion (Fig. 7).23) Baboons have a true definite RC with the tendons of SSP and ISP blending well medial to their insertion to the greater tuberosity. As in man, the tendon of TM in the baboon was much shorter than those of the spinati, but it did blend with the posterior margin of the tendon of ISP, completing the RC. Baboon can also scratch the back of its head with its upper limbs. Baboon can function with its upper limbs overhead, however, do so less in comparison with the hominoids (orangutan or chimpanzee) (Fig. 8).23) Orangutan and chimpanzee, considered advanced primates, are members of the hominoid family which also includes man. They all had a well-formed RC with definite connections between the tendons involved and can function regularly with their

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B

Fig. 8. Photographs of the true rotator cuff of the baboon show blending of the tendons of supraspinatus (SSP), infraspinatus (ISP) and teres minor (TM) on (A) the dorsal and (B) the articular surface. Cited from the article of Sonnabend and Young (J Bone Joint Surg Br. 2009;91:1632-7) with original copyright holder’s permission.23)

upper limbs overhead. They can also scratch the back of their heads with their upper limbs (Fig. 9).23)

Advantages and Disadvantages The advantage of the baboon is that it is a better animal model for the study of repair of the RC because of the similarity of the shoulder to that of man.34) However, they are rarely used in vivo study due to the large cost, complexities, facilities, and management difficulties required to maintain primates in sufficient numbers for such purposes.

Conclusion Rat, rabbit, dog, and sheep are commonly used for assessing the pathology and RC repair. However, each of these species lacks a true RC, having individual tendons which did not blend before insertion into the humerus. The lower primates and all the non-primate species, except the tree kangaroo, were neither functional overhead nor had a true RC.23) Utilizing more advanced primates, or perhaps even the tree kangaroo would be ideal and the most relevant to man as they

Characteristics of Animal Shoulder Models for Rotator Cuff Experiments Min-Cheol Kim and Myung-Sun Kim

SSP

ISP

TM

TM

ISP

SSP

Fig. 9. Photographs of the true rotator cuff of the orangutan show an almost indistinguishable appearance from that of man on the dorsal and the articular surface. SSP: supraspinatus, ISP: infraspinatus, TM: teres minor. Cited from the article of Sonnabend and Young (J Bone Joint Surg Br. 2009;91:1632-7) with original copyright holder’s permission.23)

possess a true RC. However, ethical concerns, costs, and many limitations in obtaining primates generally preclude the use of these animals for such research. Finally we should consider the differences in comparative anatomy and behavioral pattern of each animal model during performance or interpretation of RC experiments.

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