Partial Repair of Full-Thickness Rotator Cuff Tears By Guided Application of Umbilical Cord Blood Mesenchymal Stem Cells


Baseball players, weight lifters, tennis players, basketball players, and other athletes have experienced the pain and frustration of a rotator cuff injury. The rotator cuff is the capsule that surrounds the shoulder joint, in combination with the fused tendons that support the arm at the shoulder joint. A tear in any of these tendons constitute a rotator cuff tear, and it is painful, and debilitating. Furthermore, rotator cuff tears are notoriously slow healing, if they heal at all.

The main option for a rotator cuff tear is microsurgical repair of the tendon. However, as Christopher Centeno at the Regenexx blog points out, sewing together atrophied tissue does not make a lot of sense, and consequently, rotator cuff repairs by means of microsurgery can have a high percentage of re-tearing. Is there a better way?

In the journal Stem Cells and Translational Medicine, Dong Rak Kwon and his two colleagues, Gi-Young Park and Sang Chui Lee, from the Catholic University of Daugu School of Medicine in Daegu, Korea have reported the results of treating whole-thickness rotator cuff tears in rabbits with human umbilical cord blood mesenchymal stem cells (UCB-MSCs). The results are quite interesting.

Kwon and his colleagues broke a colony of New Zealand White rabbits into three groups and surgically subjected all animals to full-thickness tears in the subscapularis tendon. Because rabbits are four-legged creatures, such tears severely compromise their ability to walk, and Kwon and his team measured the ability of these rabbits to walk and the speed at which they walked. All three groups of rabbits showed about the same ability to walk: they walked at about the same speed at for the same distance before giving up.

Human umbilical cord blood-derived mesenchymal stem cell (MSC) and ultrasound images. (A): Human umbilical cord blood-derived MSCs. (B): Injection was made in the left shoulder subscapularis (SCC) full-thickness tears under ultrasound guidance. (C): Longitudinal ultrasound image showed the needle (arrows) in the left shoulder SCC of the rabbit. Abbreviations: S, mesenchymal stem cell; T, tendon.
Human umbilical cord blood-derived mesenchymal stem cell (MSC) and ultrasound images. (A): Human umbilical cord blood-derived MSCs. (B): Injection was made in the left shoulder subscapularis (SCC) full-thickness tears under ultrasound guidance. (C): Longitudinal ultrasound image showed the needle (arrows) in the left shoulder SCC of the rabbit. Abbreviations: S, mesenchymal stem cell; T, tendon.

The first group of rabbits received injections of UCB-MSCs into their rotator cuffs. These injections were guided by ultrasound so that Kwon and his colleagues were able to place the stem cells directly on the damaged tendons. The second group of rabbits received injections of hyaluronic acid (HA), which is a component of connective tissue and the synovial fluid within bursal sacs that surround and lubricated some our joints. The third group received injections of sterile saline into their joints. The animals were then examined four weeks later.

shoulder-joint

The HA- and saline-injected animals showed few changes, but the UCB-MSC-injected animals were able to walk almost twice as far as the other rabbits and almost twice as fast. When the joint tissue of these animals was examined in detail, the HA and saline-injected animals still had full-thickness rotator cuff tears, although the HA-injected animals showed more healing that then the saline-injected rabbits. When the UCB-MSC-injected animals were examined, seven of the ten animals have rotator cuffs that had healed so that the tears could be classified as partial-thickness tears rather than full-thickness tears. Furthermore, a more detailed examination of these joint revealed that they showed regeneration of the tendon and the production of tough, high-quality collagen I.

Gross morphological (A–F) and histological (G–I) findings of the subscapularis tendons in groups 1, 2, and 3. The polygon in each of the first six images depicts the area of the full-thickness subscapularis tendon tear. (A–C): Pretreatment images. (D–F): Posttreatment images. (G): Parallel arrangement of hypercellular fibroblastic bundles (arrow) was noted in group 1. (H, I): Histological findings in groups 2 and 3 showed absence of fiber bundles. Group 1 received a 0.1-ml injection of MSCs; group 2, 0.1 ml of HA; group 3, 0.1 ml of saline. Hematoxylin-and-eosin stain, ×40. Abbreviations: MSC, human umbilical cord blood-derived mesenchymal stem cell; HA, hyaluronic acid; SSC, subscapularis muscle.
Gross morphological (A–F) and histological (G–I) findings of the subscapularis tendons in groups 1, 2, and 3. The polygon in each of the first six images depicts the area of the full-thickness subscapularis tendon tear. (A–C): Pretreatment images. (D–F): Posttreatment images. (G): Parallel arrangement of hypercellular fibroblastic bundles (arrow) was noted in group 1. (H, I): Histological findings in groups 2 and 3 showed absence of fiber bundles. Group 1 received a 0.1-ml injection of MSCs; group 2, 0.1 ml of HA; group 3, 0.1 ml of saline. Hematoxylin-and-eosin stain, ×40. Abbreviations: MSC, human umbilical cord blood-derived mesenchymal stem cell; HA, hyaluronic acid; SSC, subscapularis muscle.

Collagen I is the tough material that makes tendon. When rotator cuff surgeries fail, it can be for a variety of reasons, such as poor blood supply, intrinsic tendon degeneration, fatty infiltration, or muscle atrophy (see UG Longo, et al., British Medical Bulletin 2011, 98:31-59).

Histological micrographs of tissue from group 1 rabbits. (A): Newly regenerated tendons are shown in the blue-stained fibers (black arrow; Masson’s trichrome stain; magnification, ×12.5). (B): Regenerated tendon fibers (yellow arrowhead; Masson’s trichrome stain; magnification, ×250) are connected to adjacent M fibers. (C): The regenerated tendon fibers (black arrow) stained with anti-type 1 collagen antibody. The defect was reconstructed with human umbilical cord blood-derived mesenchymal stem cells (magnification, ×100). Abbreviation: M, muscle.
Histological micrographs of tissue from group 1 rabbits. (A): Newly regenerated tendons are shown in the blue-stained fibers (black arrow; Masson’s trichrome stain; magnification, ×12.5). (B): Regenerated tendon fibers (yellow arrowhead; Masson’s trichrome stain; magnification, ×250) are connected to adjacent M fibers. (C): The regenerated tendon fibers (black arrow) stained with anti-type 1 collagen antibody. The defect was reconstructed with human umbilical cord blood-derived mesenchymal stem cells (magnification, ×100). Abbreviation: M, muscle.

However, tendon failures after surgery usually result from the production of collagen III, which is mechanically weaker than collagen I, instead of collagen I (see MF Pittenger, et al., Science 1999, 284: 143-147; V Rocha, et al., New England Journal of Medicine 2000, 342: 1846-1854). None of the animals in the other groups showed any sign of collagen I production.

This experiment shows that full thickness tears in the subscapularis tendon of the rotator cuff of rabbits, which is functionally similar to the supraspinatus in humans (see figure below), can be partially healed by the ultrasound-guided infusion of UCB-MSCs.

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If larger numbers of UCB-MSCs were implanted, it is possible that the tears would have been completely repaired. Also, it is possible that partial tears can be completely repaired by this procedure, but clearly more work is required.

Other questions also remain besides the optimal dose of the cells. What sized tears can be regenerated by this procedure? What immobilization procedures are appropriate after the stem cell injections and for how long? What are the most effective rehabilitation techniques after the surgery? These are all questions that are amenable to research so take heart athletes; a better cure is slowly, but surely on its way.

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mburatov

Professor of Biochemistry at Spring Arbor University (SAU) in Spring Arbor, MI. Have been at SAU since 1999. Author of The Stem Cell Epistles. Before that I was a postdoctoral research fellow at the University of Pennsylvania in Philadelphia, PA (1997-1999), and Sussex University, Falmer, UK (1994-1997). I studied Cell and Developmental Biology at UC Irvine (PhD 1994), and Microbiology at UC Davis (MA 1986, BS 1984).