rhBMP-12 Accelerates Healing of Rotator Cuff Repairs in a Sheep Model

Department of Clinical Sciences, Colorado State University, Fort Collins, Colorado, United States
The Journal of Bone and Joint Surgery (Impact Factor: 5.28). 11/2008; 90(10):2206-19. DOI: 10.2106/JBJS.G.00742
Source: PubMed


The success rate of rotator cuff repairs is variable. This study was performed to evaluate the ability of recombinant human bone morphogenetic protein-12 (rhBMP-12), administered in several carriers, to accelerate healing in a sheep model of rotator cuff repair.
Local retention of tracer amounts of radiolabeled rhBMP-12, added to non-radiolabeled rhBMP-12 delivered in buffer, hyaluronan paste or sponges, or Type-I or Type-I/III collagen sponges was first evaluated with use of gamma scintigraphy in a pilot study of a rat intramuscular implant model. The rhBMP-12/paste and sponge combinations were then evaluated in eight sheep each with unilateral complete detachment and subsequent double-row reattachment of the infraspinatus tendon to the proximal part of the humerus. Contralateral, normal shoulders from sixteen sheep and shoulders in which a repair had been done without administration of rhBMP-12 in fourteen sheep were also evaluated. The rhBMP-12/Type-I and Type-I/III collagen sponge combinations were each evaluated in eight additional sheep on the basis of superior efficacy. The Type-I/III collagen sponge alone was evaluated in ten sheep to examine the effect of a collagen carrier. Ultrasound imaging was performed at four and eight weeks. Radiographic evaluation, mechanical testing, and biochemical evaluation were performed at eight weeks. Histological evaluation was performed on specimens from the sites of selected repairs following mechanical testing.
The sponge carriers had longer local retention of rhBMP-12 than did the buffer or paste carriers in the rat models. All of the sheep shoulder-repair groups demonstrated ultrasound evidence of a gap between the tendon and the humeral insertion. The gap length and the cross-sectional area of the repair tissue decreased with time. The mechanical properties of the repairs treated with rhBMP-12 and hyaluronan paste were similar to those of the untreated repairs. The maximum loads for the rhBMP-12/hyaluronan sponge and rhBMP-12/collagen sponge-treated repairs were 2.1 and 2.7 times greater, respectively, than the loads for the untreated repairs and were 33% and 42% of the value for the normal tendon at eight weeks. The maximum loads for the repairs treated with rhBMP-12 and a Type-I or Type-I/III collagen sponge were 2.1 times greater than those for the repairs treated with the Type-I/III collagen sponge alone. Changes in maximum stiffness followed a similar pattern. Histological evaluation demonstrated accelerated healing of the rhBMP-12-treated repairs compared with the untreated repairs. Bone formation was observed in all repairs, and biochemical measurements were not equivalent to those of normal tendon at eight weeks.
Delivery of rhBMP-12 in a collagen or hyaluronan sponge resulted in accelerated healing of acute full-thickness rotator cuff repairs in a sheep model.
Delivery of rhBMP-12 in several sponge carriers has the potential to accelerate healing of rotator cuff repairs. Accelerated repair may allow shorter rehabilitation and an earlier return to occupational and recreational activities.

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    • "Recently, numerous growth factors, such as the bone morphogenetic proteins (BMPs), basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), insulin-like growth factor 1 (IGF 1), and transforming growth factor-b (TGF-b), were found to improve the proliferation and collagen secretion of tenocytes in vitro and to increase the biomechanical strength and accelerate the tendon-to-bone healing in vivo [9], [10], [11], [12], [13], [14], [15], [16], [17], [18]. At the same time, healing is a highly complex biological process involving the precise coordination of various growth factors. "
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    ABSTRACT: Platelet-rich products (PRP) are widely used for rotator cuff tears. However, whether platelet-rich products produce superior clinical or radiological outcomes is controversial. This study aims to use meta-analysis to compare clinical and radiological outcomes between groups with or without platelet-rich products. The Pubmed, Embase, and Cochrane library databases were searched for relevant studies published before April 20, 2013. Studies were selected that clearly reported a comparison between the use or not of platelet-rich products. The Constant, ASES, UCLA, and SST scale systems and the rotator cuff retear rate were evaluated. The weighted mean differences and relative risks were calculated using a fixed-effects model. Seven studies were enrolled in this meta-analysis. No significant differences were found for the Constant scale (0.73, 95% CI, -1.82 to 3.27, P = 0.58), ASES scale (-2.89, 95% CI, -6.31 to 0.53, P = 0.1), UCLA scale (-0.79, 95% CI, -2.20 to 0.63, P = 0.28), SST scale (0.34, 95% CI, -0.01 to 0.69, P = 0.05), and the overall rotator cuff retear rate (0.71, 95% CI, 0.48 to 1.05, P = 0.08). Subgroup analysis according to the initial tear size showed a lower retear rate in small- and medium-sized tears (0.33, 95% CI, 0.12 to 0.91, P = 0.03) after platelet-rich product application but no difference for large- and massive-sized tears (0.86, 95% CI, 0.60 to 1.23, P = 0.42). In conclusion, the meta-analysis suggests that the platelet-rich products have no benefits on the overall clinical outcomes and retear rate for the arthroscopic repair of full-thickness rotator cuff tears. However, a decrease occurred in the rate of retears among patients treated with PRP for small- and medium-sized rotator cuff tears but not for large- and massive-sized tears. Level II.
    Preview · Article · Jul 2013 · PLoS ONE
    • "RhBMP-12 in a collagen types I and III sponge gave a relative increase of 2.7-fold in the maximal load. However, the mechanical properties of the tissues were similar in both augmented and control groups of the study when normalized to the size of the tendon.[74] "
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    ABSTRACT: Lesions of the rotator cuff (RC) are among the most frequent tendon injuries. In spite of the developments in both open and arthroscopic surgery, RC repair still very often fails. In order to reduce the failure rate after surgery, several experimental in vitro and in vivo therapy methods have been developed for biological improvement of the reinsertion. This article provides an overview of the current evidence for augmentation of RC reconstruction with growth factors. Furthermore, potential future therapeutic approaches are discussed. We performed a comprehensive search of the PubMed database using various combinations of the keywords "tendon," "rotator cuff," "augmentation," "growth factor," "platelet-rich fibrin," and "platelet-rich plasma" for publications up to 2011. Given the linguistic capabilities of the research team, we considered publications in English, German, French, and Spanish. We excluded literature reviews, case reports, and letters to the editor.
    No preview · Article · Apr 2012 · International Journal of Shoulder Surgery
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    • "cartilage and tendon-like structures in vivo (Chang et al. 1994; Wo lfman et al. 1997). Administration of these BMPs after tendon injuryi na nimal models results in increasedr ates of tendonr epaira nd increased strength and stiffness of injured tendons (Aspenberg andF orslund 1999; Lou et al. 2001; Bolt et al. 2007; Seeherman et al. 2008). GDF5 has been evaluated as an inducer of spine fusion in an animal model (Jahng et al. 2004; Walsh et al. 2004) and as atreatment for degenerative disc disease in the clinic. "
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    ABSTRACT: Ectopic expression of recombinant human bone morphogenetic protein 2 (rhBMP2) induces osteogenesis, while ectopic expression of rhBMP12 and rhBMP13 induces the formation of tendon-like tissue. Despite their different in vivo activities, all three ligands bound to the type I bone morphogenic protein receptors (BMPRs), activin receptor-like kinase (ALK)-3 and ALK6, and to the type II BMPRs, activin receptor type-2A, activin receptor type-2B, and BMPR2, with similar affinities. Treatment of C3H10T1/2 cells with rhBMP2 activated SMAD signaling and induced expression of osteoblast markers including osteocalcin mRNA (Ocn). In contrast, treatment with rhBMP12 or rhBMP13 resulted in a dose-dependent induction of a tendon-specific gene (Thbs4) expression with no detectable activation of SMAD 1, 5, and 8. Differential regulation of Thbs4 and Ocn has potential utility as an in vitro biomarker for induction of tenogenic signaling. Such an assay also permits the ability to distinguish between the activities of different BMPs and may prove useful in studies on the molecular mechanisms of BMP tenogenic activity.
    Full-text · Article · Jun 2011 · Growth factors (Chur, Switzerland)
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