0
    500
    views

    What Is the Current State of Biologics for Augmenting Rotator Cuff Repairs?

    Dr. Raffy Mirzayan answers questions from ICJR about the biologic options surgeons can consider to help reduce re-tears in patients with rotator cuff tears.

    ICJR: What biologics are currently available to augment rotator cuff repair, and what does the literature say about them?

    Raffy Mirzayan, MD: Rotator cuff tears are a frequent cause of shoulder pain and disability. Between 250,000 and 400,000 rotator cuff repairs are performed annually in the United States, creating a significant impact on the healthcare system and on patients’ lives. Rotator cuff repair surgery, regardless of technique – traditional open, mini-open, arthroscopic, single row, double row – results in a high level of patient satisfaction and great clinical outcomes.

    RELATED: Register for ICJR’s 7th Annual Shoulder Course

    However, imaging studies reveal up to a 94% mechanical failure (“re-tear”) of the repairs. [1] Therefore, most of the current surgical focus is directed at reducing re-tear rates, not clinical improvement.

    Better terminology should be considered to define mechanical failure. As used in the literature, the term “re-tear” implies that the tendon healed to the tuberosity and then tore again. A more universal terminology – such as “structural integrity” rate – should be used in the literature to describe the actual state of the tendon-bone interface.

    To better understand why rotator cuff repairs fail, we need to understand when they fail. Several sequential imaging studies showed that most rotator cuff “re-tears” within 3 to 4 months after the initial repair. [2-4] No re-tears occurred after 6 months. 

    What these studies demonstrate is that failures happen early on, and that rotator cuff healing is much slower than expected. Despite advances in implants and mechanically superior repairs, our current repairs do not hold up long enough for healing to occur. Therefore, we need to either increase the mechanical strength or expedite the biologic healing of rotator cuff repairs. 

    The weak link in the rotator cuff repair construct is the suture-tendon interface (Figure 1). [2,5-7] Suture pull-out is caused by the poor tissue quality of the rotator cuff tendon.  Codman suggested that degenerative changes occur in the rotator cuff tendons as we age, and therefore, losing their ability to retain the sutures.

      

    Figure 1. Shoulder arthroscopy demonstrating a re-tear of the rotator cuff with the suture and suture knots still present.

    Surgeon-controlled variables – such as anchor type, suture material, knot type, stitch configuration, size and shape of a tissue-penetrating instrument, and size of the tissue bite – can strengthen the repair (increase the load to failure) at time zero.

    Biologic augmentation can play a substantial role in strengthening this interface.  Dermal allografts, also known as acellular dermal matrices (ADM) or “patches,” have been extensively studied in the laboratory [7-9] and clinically, [10] and they can significantly increase the ultimate load to failure in vitro and reduce re-tear rates. Superior suture pull-out strength has also been demonstrated by multiple bench and pre-clinical studies. [8,11]

    Therefore, ADMs play a dual role of strengthening the repair while allowing infiltration of host cells and growth factors to potentially promote healing at the repair site.

    There are several commercially available ADMs with different methods of processing and sterilization and different handling characteristics. ADMs have typically been manufactured in large sizes, which makes it challenging to use them arthroscopically to augment rotator cuff repairs. Smaller sizes have recently been developed and commercialized, and they can easily be used arthroscopically (Figures 2a-b).

     

    Figure 2a. Arthroscopic, double-row, transosseous equivalent rotator cuff repair with small commercially available acellular dermal matrix (ADM) (black arrows) incorporated into the repair to increase the ultimate load to failure.

     

    Figure 2b. Postoperative MRI 6 months after repair demonstrating a healed rotator cuff with the ADM (white arrow) integrated onto the rotator cuff tendon.

    The currently available products for enhancement of biologic healing of rotator cuff tears focus on the cellular level to attract and activate cells to release growth factors, which will stimulate the healing of tendon to bone.

    Platelet rich plasma (PRP) is a concentrate of the patient’s own blood to produce an injection of platelets that can promote healing. The release of growth factors from alpha granules by platelets enhances cell proliferation of tenocytes and promotes the synthesis of extracellular matrix cell proliferation, chemotaxis, cell differentiation, and angiogenesis to augment the healing process. [12]

    The literature is inconsistent on the outcomes of PRP use in rotator cuff repair. Several studies have demonstrated that although the use of PRP made no difference in the clinical outcomes after rotator cuff repairs, it did have an impact on structural integrity, indicating that it promoted healing of tendon to bone.

    In some studies, PRP did not have an effect on the structural integrity rate, [13] but in others, PRP improved structural integrity rates.

    In a meta-analysis of 13 reports published between 2010 and 2014, Vavken et al [14] found that the risk ratio for re-tear was 0.60 for small- and medium-sized tears (<3 cm), consistent with a significant difference in favor of PRP use (P = .038). In tears greater than 3 cm in anterior-posterior length, the PRP-treated group exhibited decreased re-tear rates after double-row repair.

    In another meta-analysis, this one involving 5 Level I studies, Cai et al [15] also found that although there were no statistically significant differences in overall outcome scores (P >0.05), patients with small-to-moderate full-thickness tears who were treated with PRP exhibited better healing (P <0.03).

    A contributing factor to the inconsistency in the literature is that not all PRP formulations are the same: The commercially available systems produce varying concentrations of PRP. A single patient can have high levels of variability in platelet concentration throughout the day.

    Other factors can have an effect on the healing potential and inconsistency in findings, such as activation of platelets (usually with thrombin) to create a gel or clot and the amount of white blood cells.

    Therefore, one must read the PRP literature carefully with regard to rotator cuff repair to make an accurate comparison between studies.

    ICJR: Are there any other promising biologic options?

    Dr. Mirzayan: Yes, there are: stem cells from adipose tissue, bone marrow aspirate, and amnion.

    Currently, only adipose-derived stem cells and bone marrow aspirate are being commercially used. Both types of cells can be obtained in the office with minimal donor site morbidity.

    Bone marrow aspirate concentrate has been used for decades in Europe, with a long-term follow-up study [4] detailed below showing significant benefit in rotator cuff repair surgery.

    Hernigou et al [4] performed an arthroscopic single-row repair on 45 matched pairs of patients with rotator cuff tears less than 3 cm. Patients were matched for age, gender, dominance, and tear size. In addition to surgery, the treatment group received concentrated bone marrow aspirate at the time of the repair.

    The patients were followed clinically and with imaging studies, including monthly ultrasound for the first 24 months and MRIs at 3, 6, 12, and 24 months and 10 years postoperatively.

    The authors found that injection of bone marrow-derived mesenchymal stem cells (MSC) during rotator cuff repair enhanced the healing rate and improved the quality of the repaired surface. All 45 repairs (100%) with MSC augmentation had healed by 6 months versus 30 of 45 repairs (67%) without MSC treatment. 

    Injection of bone marrow concentrate also prevented further ruptures during the next 10 years. At the 10-year follow-up, intact rotator cuffs were found in 39 of the 45 patients (87%) in the MSC-treated group, but just 20 of the 45 patients (44%) in the control group.

    Another significant finding in this study was the lack of re-tears in patients who received bone marrow aspirate MSC in the first 6 months after surgery. In contrast, 8 of the control patients (17.8%) had a re-tear between 2 and 3 months after surgery, and an additional 8 (17.8%) had a re-tear between 3 and 6 months after surgery, with an average time to re-tear of 3.4 months. This implies that the bone marrow concentrate expedited healing in the first few months of repair.

    A recent study by Kim et al [16] followed 35 matched-pair arthroscopic rotator cuff repairs treated with and without injection of adipose derived mesenchymal stem cells (ADMSC), based on sex, age, and lesion size for an average of 28 months. Patients were also evaluated with a postoperative MRI at a minimum of 1 year. Although there was no difference in the clinical improvement, MRI demonstrated a significant reduction in the “re-tear” rate: 28.5% in the control group versus 14.3% in the ADMSC group (P<0.001). 

    The use of amniotic tissue is new to the field of orthopaedic surgery, but it has been safely and successfully used in other fields of medicine.

    Its potential application in rotator cuff surgery is promising. One of the mechanisms by which amnion can play a role in rotator cuff repair surgery is by its potent inhibition of matrix metalloproteinases, which is a family of zinc-dependent proteases that collectively degrade essentially all the components of the extracellular matrix. [17-19]

    Increased levels of MMP have been demonstrated in torn rotator cuff tendons in animals and in humans, and inhibition of MMPs has been shown to have significant effects at the tendon-bone interface. [20,21] Amnion is a known potent source of MMP inhibitor [19] and can potentially play a role in rotator cuff healing.

    Although there are several ongoing studies to identify and perfect a drug that can be used to modulate MMP activity, there are currently no drugs approved by the US Food and Drug Administration that can be used for this application.

    Because amnion is an allograft tissue, it can be used currently to inhibit MMP activity after rotator cuff repair and potentially expedite the healing of tendon to bone.

    Further research is needed to understand the optimal mechanical repair and biologic enhancement of the healing response for all types of biologic options to help manage patients with rotator cuff tears.

    About the Expert

    Raffy Mirzayan, MD is Co-Director of Sports Medicine, Director of Cartilage Restoration, and Director of Orthopaedic Resident Education at Kaiser Permanente, Southern California, in Baldwin Park, California. He is also Clinical Professor of Orthopaedic Surgery at USC Keck School of Medicine, Los Angeles, California.

    Disclosures

    Dr. Mirzayan has disclosed that he receives royalties from Wolters Kluwer and Thieme; honorarium from Arthrex; and research grants from Arthrex, Joint Restoration Foundation, and BioD LLC. He has stock in Alignmed.

    References

    1. Galatz LM, Ball CM, Teefey SA, Middleton WD, Yamaguchi K. The outcome and repair integrity of completely arthroscopically repaired large and massive rotator cuff tears. J Bone Joint Surg Am. 2004;86-a:219-224.
    2. Miller BS, Downie BK, Kohen RB, Kijek T, Lesniak B, Jacobson JA, Hughes RE, Carpenter JE. When do rotator cuff repairs fail? Serial ultrasound examination after arthroscopic repair of large and massive rotator cuff tears. Am J Sports Med. 2011;39:2064-2070.
    3. Iannotti JP, Deutsch A, Green A, Rudicel S, Christensen J, Marraffino S, Rodeo S. Time to failure after rotator cuff repair: a prospective imaging study. J Bone Joint Surg Am. 2013;95:965-971.
    4. Hernigou P, Flouzat Lachaniette CH, Delambre J, Zilber S, Duffiet P, Chevallier N, Rouard H. Biologic augmentation of rotator cuff repair with mesenchymal stem cells during arthroscopy improves healing and prevents further tears: a case-controlled study. Int Orthop. 2014;38:1811-1818.
    5. Ponce BA, Hosemann CD, Raghava P, Tate JP, Sheppard ED, Eberhardt AW. A biomechanical analysis of controllable intraoperative variables affecting the strength of rotator cuff repairs at the suture-tendon interface. Am J Sports Med. 2013;41:2256-2261.
    6. Cummins CA, Murrell GA. Mode of failure for rotator cuff repair with suture anchors identified at revision surgery. J Shoulder Elbow Surg. 2003;12:128-133.
    7. Barber FA, Herbert MA, Boothby MH. Ultimate tensile failure loads of a human dermal allograft rotator cuff augmentation. 2008;24:20-24.
    8. Barber FA, Herbert MA, Coons DA. Tendon augmentation grafts: biomechanical failure loads and failure patterns. 2006;22:534-538.
    9. Beitzel K, Chowaniec DM, McCarthy MB, Cote MP, Russell RP, Obopilwe E, Imhoff AB, Arciero RA, Mazzocca AD. Stability of double-row rotator cuff repair is not adversely affected by scaffold interposition between tendon and bone. Am J Sports Med. 2012;40:1148-1154.
    10. Barber FA, Burns JP, Deutsch A, Labbe MR, Litchfield RB. A prospective, randomized evaluation of acellular human dermal matrix augmentation for arthroscopic rotator cuff repair. 2012;28:8-15.
    11. Adams JE, Zobitz ME, Reach JS, Jr., An KN, Steinmann SP. Rotator cuff repair using an acellular dermal matrix graft: an in vivo study in a canine model. 2006;22:700-709.
    12. Jo CH, Kim JE, Yoon KS, Shin S. Platelet-rich plasma stimulates cell proliferation and enhances matrix gene expression and synthesis in tenocytes from human rotator cuff tendons with degenerative tears. Am J Sports Med. 2012;40:1035-1045.
    13. Vavken P, Sadoghi P, Palmer M, Rosso C, Mueller AM, Szoelloesy G, Valderrabano V. Platelet-Rich Plasma Reduces Retear Rates After Arthroscopic Repair of Small- and Medium-Sized Rotator Cuff Tears but Is Not Cost-Effective. Am J Sports Med. 2015;43:3071-3076.
    14. Warth RJ, Dornan GJ, James EW, Horan MP, Millett PJ. Clinical and structural outcomes after arthroscopic repair of full-thickness rotator cuff tears with and without platelet-rich product supplementation: a meta-analysis and meta-regression. 2015;31:306-320.
    15. Cai YZ, Zhang C, Lin XJ. Efficacy of platelet-rich plasma in arthroscopic repair of full-thickness rotator cuff tears: a meta-analysis. J Shoulder Elbow Surg. 2015;24:1852-1859.
    16. Kim YS, Sung CH, Chung SH, Kwak SJ, Koh YG. Does an injectionof adipose-derived mesenchymal stem cells loaded in fibrin glue influence rotator cuff repair outcomes? A clinical and magnetic resonance imaging study. Am J Sports Med. 2017 Jul;45(9):2010-2018. doi: 10.1177/0363546517702863. Epub 2017 Apr 27.
    17. Lo IK, Marchuk LL, Hollinshead R, Hart DA, Frank CB. Matrix metalloproteinase and tissue inhibitor of matrix metalloproteinase mRNA levels are specifically altered in torn rotator cuff tendons. Am J Sports Med. 2004;32:1223-1229.
    18. Choi HR, Kondo S, Hirose K, Ishiguro N, Hasegawa Y, Iwata H. Expression and enzymatic activity of MMP-2 during healing process of the acute supraspinatus tendon tear in rabbits. J Orthop Res. 2002;20:927-933.
    19. Litwiniuk M, Bikowska B, Niderla-Bielinska J, Jozwiak J, Kaminski A, Skopinski P, Grzela T. Potential role of metalloproteinase inhibitors from radiationsterilized amnion dressings in the healing of venous leg ulcers. Mol Med Rep. 2012;6:723-728.
    20. Bedi A, Kovacevic D, Hettrich C, Gulotta LV, Ehteshami JR, Warren RF, Rodeo SA. The effect of matrix metalloproteinase inhibition on tendon-to-bone healing in a rotator cuff repair model. J Shoulder Elbow Surg. 2010;19:384-391.
    21. Bedi A, Fox AJ, Kovacevic D, Deng XH, Warren RF, Rodeo SA. Doxycycline-mediated inhibition of matrix metalloproteinases improves healing after rotator cuff repair. Am J Sports Med. 2010;38:308-317.