Gene-regulated cells, tissue engineered scaffold show promise for rotator cuff repair

Despite the best surgical effort, obtaining healing after rotator cuff repair remains a challenge, according to one orthopedic surgeon.

“In one study from 2004, up to 90% of massive rotator cuff repairs failed,” William N. Levine, MD, said at Orthopedics Today Hawaii 2011. In his talk, Levine reviewed how biologic enhancement might improve healing.

Rotator cuff injuries may fail to heal because of insufficient gene expression, insufficient undifferentiated cells at the healing site or excessive loads on the healing tendon (tendon-bone interface motion), Levine said.

Postoperative inflammation may be the cause. Fetal mouse wound models have demonstrated no scar tissue at 72 hours, he said. Pediatric surgeons performing intrauterine fetal surgery see similar results. There is no macrophage accumulation and thus, little or no inflammation, Levine said.

“So in non-fetal wound healing, you get inflammation and that leads to scar tissue. So the question we need to try to address is can we inhibit scar formation and typical wound healing with biological augmentation,” he said.

The potential of growth factors

Scott A. Rodeo, MD, of Hospital for Special Surgery, has done a series of studies on osteoinductive bone protein extracts. In one study, his research group used BMP-2 through -7 and a fibroblast growth factor in a sheep infraspinatus model. The MRI results showed that the volume of newly formed bone and soft tissue was increased in the BMP-treated animals, Levine said.

William N. Levine

Although the BMP had increased load-to-failure at 6 and 12 weeks, when the researchers normalized for tissue volume, they saw no difference between the groups. These particular growth factors resulted in the formation of poor-quality scar tissue; they could not reproduce the desired tendon-bone interface, Levine said.

Another sheep infraspinatus study used the novel recombinant BMP-12, which is expressed at tendon insertion sites during embryologic development, Levine said. This study showed increased load-to-failure. All rhBMP-12 repairs were stronger than controls, which suggested that this growth factor may play an important role in cuff healing.

Platelet-rich plasma (PRP) has multiple potential growth factors. “And we know that platelets are stimulated to release these factors after exposure to collagen and/or thrombin and calcium,” he said.

Researchers have performed two prospective, randomized studies on PRP. In Steven C. Weber, MD’s study, there was a trend toward improved results in the non-PRP group but identical early clinical results. In the second study, there was no clinical difference. The researchers saw some improved vascularity in the PRP group, which warrants further investigation, Levine said.

No clinical evidence to support PRP

So at this point, despite tremendous laboratory and animal study evidence that highlight the potential of PRP, there is no clinical evidence to support its widespread use as an augment for cuff repair, he said.

Next up are the matrix metalloproteinases (MMPs), a family of zinc-dependent proteases that maintain and remodel the extracellular matrix of connective tissues, Levine said. MMP-1 cleaves collagen fibrils, MMP-3 regulates extracellular matrix degeneration and remodeling, and MMP-9 degrades smaller collagen fragments.

“MMP 1 and 9 are bad actors, and MMP 3 is a good actor,” Levine said.

Stefan Lakemeier MD’s study suggested operating on these patients early rather than waiting until the tear is large and retracted may improve the biological environment, Levine said. If researchers could inhibit MMPs, repair-site degradation would be decreased, potentially yielding better remodeling and healing.

A rat study by Asheesh Bedi, MD and colleagues at HSS, MD, showed that doxycycline significantly increased collagen organization. “Modulation of MMP activity after cuff repair may augment tendon-bone healing,” Levine said. “We’re starting to see a couple of different things now where we might be able to modulate that healing environment.”

Mesenchymal stem cells (MSCs) are multipotent fibroblast-like cells that differentiate into fibroblasts, osteoblasts, adipocytes, etc. A study by Lawrence V. Gulotta, MD, looking at 98 Lewis rats yielded no difference when just using the stem cells. “[The researchers] thought stem cells would be terrific, and in this study, they could not prove that,” Levine said.

When these researchers modified the MSCs, the MMP had increased fibrocartilage, ultimate load-to-failure, ultimate stress compared to the MSC group.

Helen Lu, PhD and colleagues at Columbia University have been working on a novel, biomimetic, biodegradable scaffold. Preliminary study results indicate that the scaffolds did not compromise biomechanics, he said.

Their recent study in Lewis rats showed that the nanofiber scaffold supports cell viability and proliferation and regenerated both the non-calcified and calcified fibrocartilage interface. This finding certainly is exciting and warrants further investigation as it is one of the few studies to show that both the non-calcified and calcified fibrocartilage interfaces can be recreated. – by Colleen Owens

References:

• Bedi A, et al. Doxycycline-mediated inhibition of matrix metalloproteinases improves healing after rotator cuff repair. Am J Sports Med. 2010;38(2):308-317.
• Gulotta LV, et al. Application of bone marrow-derived mesenchymal stem cells in a rotator cuff repair model. Am J Sports Med. 2009;37(11):2126-2133.
• Lakemeier S, et al. Expression of matrix metalloproteinases 1, 3, and 9 in differing extents of tendon retraction in the torn rotator cuff. Knee Surg Sports Tramatol Arthrosc. 2011; Jan. 11 (e-pub ahead of print)
• Levine WN. Biologic enhancement — Is it ready for prime time yet? Presented at Orthopedics Today Hawaii 2011. Jan. 16-19, 2011. Koloa, Hawaii.
• Rodeo SA, et al. Biologic augmentation of rotator cuff tendon-healing with use of a mixture of osteoinductive growth factors. J Bone Joint Surg (Am). 2007;89:2485-2497.
• Weber SC. Platelet-Rich Fibrin Matrix in the Management of Arthroscopic Repair of the Rotator Cuff: A Prospective, Randomized Study 2010 American Shoulder and Elbow Surgeons Specialty Day Meeting. March 19, 2010. New Orleans.

• William N. Levine, MD, can be reached at the Columbia University Medical Center, 622 W 168th St., PH-1117, New York, New York 10032; 212-305-0762; email: wnl1@columbia.edu.
• Disclosure: Levine receives basic science support from Arthrex, Zimmer and Smith & Nephew.