In orthopedic literature, the phenomenon of adipocyte accumulation in and around skeletal muscle is referred to by a variety of names: fatty infiltration, fatty degeneration, or fatty change. A histologic study, by Meyer and colleagues [77], showed normal-appearing muscle fibers with adipocyte infiltration, but no degeneration—suggesting fatty infiltration as the appropriate terminology. Itoigawa and colleagues [78], however, believe the “infiltrating” adipocytes to actually be differentiating from muscle stem cells and therefore believed fatty degeneration to be accurate. As this debate is ongoing, this chapter will use these terms interchangeably.

Muscle atrophy is commonly seen with disuse and the unloading of tensile force on the skeletal muscle. Yet, the rotator cuff is unique in that when injured, a fatty-fibrous degeneration, in addition to disuse atrophy, is observed. It is currently unclear if fatty degeneration of the rotator cuff is suggestive of a failed repair mechanism that predisposes to tears or if it is simply intrinsic to the normal degenerative process [79].

The tear of the rotator cuff tendon, detachment from the bone, and subsequent unloading of stress on the rotator cuff tendon and muscle lead to changes in the muscle and tendon structure. Structural changes include myofibril disorganization—decreased sarcomere length and number—followed by a reduction in muscle mass and volume rather than fiber death [80]. This disuse atrophy, resulting from an extended period of muscle retraction, leads to a pattern of progressive fibrosis and increased fat content that accumulated at intrafascicular, extrafascicular, and intratendinous sites within the muscle [77, 81, 82]. Fatty infiltration and muscle atrophy are seen throughout the tendon and muscle [79]. The degree of fatty infiltration and muscle atrophy progression in rotator cuff tears is positively correlated with patient age, tear size (length and width), location, full-thickness involvement [83], and chronicity [81] of the tear. Suprascapular neuropathy or denervation secondary to muscle retraction and resulting neuropraxia has also been implicated in contributing to the degree of these pathologic changes [84–89].

Muscle atrophy and fatty degeneration are progressive and often irreversible adverse histologic changes that occur throughout the tendon and muscle [82, 90, 91]. While surgical repair may prevent further progression of muscle atrophy and fatty degeneration, it often does not reverse established preoperative fatty degeneration and atrophy [90–94]. Many of the histologic changes noted in rotator cuff tendon are also reflected in the rotator cuff muscle. The ECM is extensively reorganized and remodeled by the same family of matrix metalloproteinases (MMPs) during the progression of muscle atrophy following a rotator cuff tear. MMP-2, MMP-9, and MMP-13 overexpression has been associated with muscle atrophy [82, 90, 91]. It has also been hypothesized that the Akt-mammalian target of rapamycin (mTOR) pathway is central to the development of muscle atrophy [95]. Increased mTOR and Akt activity is associated with an inhibition of nuclear factor kappa B (NF-κB) and forkhead transcription factor (FOXO). Both NF-κB and FOXO regulate increased expression of proteins associated with muscle atrophy [96, 97]. In chronic human supraspinatus tears, these proteinases along with NF-κB were upregulated [98] (Fig. 1.3).

The exact source of the adipocytes that contribute to fatty degeneration of the rotator cuff is still not certain. The current hypotheses are (1) preexisting adipocytes are stimulated and proliferate within the muscle, (2) resident pluripotent stem cells are signaled to differentiate into mature adipocytes, and (3) adipocytes are recruited from extramuscular sources [78]. Of the three, the current molecular research indicates that the differentiation of local stem cells, known as mesenchymal stem cells (MSCs), appears to be the most likely source of adipocytes during fatty degeneration. Transcription factors of the MRF family implicated in the differentiation of myoblasts into mature myocytes are MYoD, Myf-5, myogenin, and MRF4 [100, 101]. Furthermore, two different families of transcription factors are believed to differentiate pre-adipocytes into mature adipocytes; these are CCAT/enhancer-binding proteins (C/EBPs) and peroxisome proliferator-activated receptors (PPARs) [78, 102, 103]. In an ovine model of rotator cuff tear, real-time PCR analysis identified increases in Myf-5 and PPARγ expression after tenotomy and subsequent increases in Myf-5 and C/EBP_β expression post repair [104]. Furthermore, the Wnt signaling pathway has also been identified to be central to adipogenesis of MSCs [78, 105–107]. More specifically, in vitro culture of a murine myogenic cell line (C2C12) in an adipogenic culture media resulted in diminished Wnt10b expression and increased expression of PPARγ and C/EBPα; this expression pattern was subsequently confirmed in vivo by gene expression analysis in a rotator cuff tear rat model [78].

Fatty degeneration predominates in the distal portion of the rotator cuff muscle near the musculotendinous junction [78, 88, 91, 108]; at this region of the cuff, there also exists a more sustained decrease in Wnt10b as well as an increase in PPARγ and C/EBPα [78]. Two mechanisms are implicated in driving these changes in protein signaling. The first is muscle retraction: mechanical stretching of muscle tissue was shown to increase Wnt10 signaling and inhibit adipogenesis [109]. Therefore, retraction of muscle tissue is thought to have the opposite effect on Wnt signaling and thus promotes adipocyte proliferation. The second mechanism is that local hypoxia can contribute to adipocyte proliferation through trans-differentiation of myoblasts [106]. This trans-differentiation is associated with increased PPARγ expression, which is also observed during hypoxic conditions [106]. Furthermore, two different studies have found increased expression of hypoxia-inducible factor 1 and VEGF to be associated with the development of fatty infiltration [62, 110].

The normal insertion of tendon into the bone is comprised of four distinct zones: tendon, unmineralized fibrocartilage, mineralized fibrocartilage, and bone [111]. Following rotator cuff repair, the tendon-to-bone interface does not recapitulate the native enthesis but rather forms a reactive scar [112, 113].

One suggestion is that healing is affected by the vascular supply to the rotator cuff [114]. As described in the aforementioned histologic studies [37, 38], vascular proliferation is often noted in torn rotator cuff muscle. In contrast, Gamradt and colleagues [115] have found that the healing cuff tendon is fairly avascular and that a significant amount of the vascular supply to the healing cuff originates from the bone [46, 116].

Other than decreased vascular supply, it is also believed that poor cuff healing is a result of disorganized temporal expression of cytokines. Furthermore, slow and incomplete bony ingrowth into the tendon from the prepared tuberosity, inflammatory cells that precipitate scar formation at tendon-bone interface, and a scarce population of undifferentiated stem cells at the bone-tendon interface all may prevent proper healing [112].

Three stages are involved in the degeneration and healing of the rotator cuff: (1) inflammatory phase, (2) repair phase, and (3) remodeling phase [117]. Various cytokines are expressed throughout different time points within these three stages to facilitate proper tendon-to-bone healing. During the inflammatory phase, the fibrovascular scar tissue is produced in the rotator cuff following an infiltrate of mast cells and macrophages [56]. These macrophages will secrete signaling molecule such as transforming growth factor β1 (TGF-β1): a cytokine known to increase collagen formation and proteinase activity [118]. After the inflammatory phase, fibroblasts are activated within the repair phase. These activated fibroblasts express a variety of cytokines, which are described below.

PDGF-β is believed to play a central role in the repair of tendons and ligaments. It has been shown to promote chemotaxis, extracellular matrix production, surface integrin expression, cell proliferation, and revascularization in fibroblasts [119–122]. Improved mechanical properties stem from PDGF-β stimulating increased collagen I production. In an ovine model of rotator cuff repair, sheep treated with PDGF-β had improved histologic scores and load-to-failure rates [123]. The TGF-β family of proteins is integral to normal fetal development, modulation of scar tissue after a wound, and tendon-to-bone healing [112]. Varied expression levels of two different TGF-β isoforms modulate the amount of scar that forms at the tendon-bone healing site [124, 125]. Treatment of the healing enthesis with TGF-β3 produces a more favorable collagen I to collagen III ratio to withstand increased tensile strength [126]. The BMP family, which is a subset of the TGF-β superfamily, also plays a role in healing of the enthesis via bony ingrowth. BMP-12, BMP-13, and BMP-14 are three cytokines [127], which contribute to the synthesis of fibrocartilage, induction of neotendon, and ligament formation. During the initial inflammatory phase of tendon healing, IGF-1 is activated. It contributes to chemotaxis as well as proliferation of fibroblasts and inflammatory cells to the site of injury [112]. In vivo, it increases cellular proliferation, enhances matrix synthesis, improves tendon mechanical properties, and reduces time to functional recovery [128–130]. FGF-1 and bFGF (also known as FGF-2) are both central modulators of angiogenesis and mesenchymal cell mitogenesis [112]. The more potent mitogen is bFGF, and during healing it helps initiate the formation of granulation tissue [131–133] and induction of fibroblast collagenase with a dose-dependent increase in type III collagen expression levels [134, 135]. Furthermore, bFGF expression by fibroblasts is also associated with improved tendon healing [134–137], cell proliferation, cell migration, collagen production, and angiogenesis [138–141]. Increased vascular supply is also central to proper rotator cuff healing. Vascular endothelial growth factor (VEGF) contributes to neovascularization and, in several models, has been observed at the site of the healing enthesis [142–145].

Just as rotator cuff pathology is a degenerative process resulting from a variety of influences, proper rotator cuff healing is also a multifactorial process. Therefore, rotator cuff repairs often fail through a combination of barriers to proper healing, which can be characterized into three broad categories: biologic factors, technical errors, and traumatic failure [114], of which the biologic factors may be the most pertinent. The biologic factors that underlie improper rotator cuff healing are the patient age, level of fatty degeneration, amount of muscle atrophy, cuff vascularity, and tear size. Furthermore, medical comorbidities such as diabetes, nicotine use, and NSAID use have also been found to be detrimental in rotator cuff healing.

Fatty degeneration and muscle atrophy are both independent predictors of poor functional outcomes following rotator cuff repair [90]. Increases in fatty infiltration and muscle atrophy can increase the tension applied to the repair site as these degenerative changes decrease the compliance of the musculotendinous unit. This phenomenon has been confirmed in both animal models and clinical studies [146]. Postoperative radiographic assessment demonstrates higher re-tear rates to be associated with an increased degree of fatty degeneration and muscle atrophy [90, 147, 148]. Although degenerative changes in the rotator cuff muscle are often irreversible [82, 90, 91], the further progression of these changes can be diminished by surgical repair [90–94]. Therefore, earlier repair can lead to greater recovery of muscle and tendon elasticity [149], lower re-tear rates, and improved clinical results [150].

As mentioned earlier, there is a positive correlation between patient age and cuff tear incidence. Several studies have found that increasing patient age is also correlated with decreased healing rates postoperatively [151–157]. One contributing factor could be insufficient postoperative vascular supply in elderly patients. Contrast-enhanced ultrasound suggests that blood supply to the tendon has an effect on healing [59, 114, 115], and diminished blood supply to the rotator cuff is observed with increasing age, especially in patients over 40 [59].

There are multiple factors intrinsic to the cuff tear itself that can also contribute to poor outcomes following repair. These include the number of cuff tendons torn [154], the quality of the cuff tendon, as well as the initial tear size [152, 154–157]. A study by Nho and colleagues [157] established that with each centimeter increase in tear size, there is a twofold increase in risk of persistent tear or re-tear following repair. Finally, postoperative NSAID (indomethacin and celecoxib) administration in a rat model has been demonstrated to effect tendon-to-bone healing. Animals treated with NSAIDs showed decreased collagen organization and maturation as well as a decreased load-to-failure ratio at 4- and 8-week time points following rotator cuff repair [158]. However, there have been no clinical studies to confirm the detrimental effects of NSAID use on rotator cuff healing.

The effect of a massive rotator cuff tear on the biomechanics of the shoulder can only be understood in the context of normal shoulder biomechanics. The purpose of the shoulder is to position the hand in space, and the glenohumeral joint has the greatest range of motion of any joint to accomplish this function. The design of the shoulder provides a balance between motion, force transmission, and stability: the rotator cuff contributes to all three.

Shoulder motion is complex, but a reasonable understanding of it can be gained by considering the shoulder through the lens of planar and 3D motion. Planar motion consists of spinning, sliding, and rolling. Spinning is essentially rotation of the humeral head on the fixed glenoid; the instantaneous center of rotation is at the center of the humeral head. Sliding is translation of the humerus on the glenoid, and the instantaneous center of the rotation is at the center of glenoid curvature. Finally rolling is a motion between moving and fixed segments where the contact points are constantly changing [159]. The shoulder is essentially a spherical spinning joint with a small amount of translation [160] (Fig. 1.4). Alternately shoulder motion can be thought of in terms of Eulerian angles as along the x axis (along the humeral shaft), y axis (lateral to the scapular plane), and the z axis (perpendicular to the scapula). Shoulder motion can be described by angular motion in those planes and is known to be sequence dependent [159, 161] (Fig. 1.5).

The exact contribution of each aspect of the cuff to shoulder motion remains a subject of great debate. In general, however, what is known is that the supraspinatus assists the deltoid in some capacity to elevate the humerus, and it also externally rotates the arm [162–166]. Whether this is primarily after the first 30° of abduction as postulated remains undetermined, many authors have argued that in fact the supraspinatus is likely most important in the first 30° of abduction as that is where its mechanical advantage is greatest [162, 164, 167]. The subscapularis internally rotates the humerus, and the infraspinatus and teres minor externally rotate the humerus [166]. The subscapularis, infraspinatus, and teres minor also may elevate or depress the humerus depending on the position of the humerus. The inferior cuff likely contributes to some aspect of abduction though this is probably as a stabilizer [164, 168].

The rotator cuff also provides a significant contribution to the stability of the glenohumeral joint. Stability of the glenohumeral joint is provided by a combination of static and dynamic stabilizers. The static stabilizers primarily contribute to stability at the extremes of joint motion and consist of both soft tissue and bony components; but they are mostly independent of the cuff. The glenoid itself provides some stability via approximately 25–30 % contact with humeral head, which is increased to 33 % by an intact labrum. The glenohumeral articulation, even when the labrum is included, is shallow and relatively unstable, but stability at the extremes of motion is greatly increased by the ligamentocapsular structures. The coracoacromial ligament is a key superior stabilizer of the shoulder; the superior glenohumeral ligament prevents inferior subluxation; the middle glenohumeral ligament blends with the subscapular tendon and provides anterior stability especially in mid-abduction and external rotation; the inferior glenohumeral ligament functions as a primary anterior-posterior stabilizer in abduction. The inferior glenohumeral ligament’s anterior band contributes stability in flexion or external rotation, whereas its posterior band is the key ligamentous stabilizer in extension [169]. Finally negative intra-articular pressure prevents subluxation, especially inferiorly [170, 171].

While these structures are important to stability of the shoulder, especially at the extremes of motion, the cuff is an important component of dynamic shoulder stabilization. In fact, it is probably the major stabilizer in normal shoulder range of motion. All muscles of the shoulder, especially the rotator cuff, provide passive resistance to humeral displacement, which is demonstrated by the fact that muscle removal but not cuff paralysis significantly increased the range of motion of the joint [164, 172]. The muscles of the rotator cuff also provide stability through a barrier effect. The anterior barrier to subluxation is provided by subscapularis, and superiorly the supraspinatus provides a spacer between the head and acromion [173, 174].

Most important, though, is contraction of the cuff musculature, which is probably essential in creating joint compression via the “compression-contracture” model of stability. The contraction of the cuff musculature both centers the head and compresses the head against the glenoid concavity which in turn prevents lateral translation [42, 164]. The balanced compression of the anterior and posterior aspects of the cuff leads to the idea of force coupling first suggested in the work of Inman and later Saha [175, 176]. The long head of the biceps tendon, often abnormal in the setting of rotator cuff injury, may help compress the head and likely help compensate for the loss of stability with cuff injury [177]. Overall the muscles of the rotator cuff are key to glenohumeral stability and allow the other muscles of the shoulder to move the stabilized glenohumeral joint.

The final component of shoulder biomechanics that bears examination is the force generated by the muscles across the glenohumeral joint. Joint reaction forces are greatest at 90° of abduction, as are joint contact pressure, though only in the setting of an intact cuff creating normal force coupling [178, 179]. Massive cuff tears decrease this effect, but small isolated tears of the supraspinatus do not appear to have a major effect (Fig. 1.6) [178].

Multiple studies have attempted to determine the activity of the cuff muscles in various arm functions aside from generation of force coupling. Duchenne’s earliest studies used galvanic measures, but more recent studies have primarily utilized EMG. The majority of studies have examined the relative importance of the supraspinatus and the deltoid to arm abduction. It remains subject to debate, but the supraspinatus is likely most essential at the generation of abduction, though if this is due more to stabilization as part of the cuff or due to its moment arm giving it a mechanical advantage is unclear. It also is likely a key centralizer of the humeral head due to the location of its moment arm [180]. Meanwhile the infraspinatus and teres minor work as humeral head depressors, but as noted above that is position dependent [164]. However, overall it seems that the cuff is most important for stabilization as in vivo EMG studies suggest that the cuff musculature is activated prior to other muscles in shoulder motion [181].