rhBMP-12 Accelerates Healing of Rotator Cuff Repairs in a Sheep Model
ABSTRACT 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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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.Growth factors (Chur, Switzerland) 06/2011; 29(4):128-39. DOI:10.3109/08977194.2011.593178 · 3.09 Impact Factor
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ABSTRACT: This study was performed to determine the effects of fibroblast growth factor-2 (FGF-2) on monolayer expansion of equine tendon- and bone marrow-derived cells prior to culture with autogenous acellular tendon matrix and insulin-like growth factor-I (IGF-I). Progenitor cells were isolated from six young adult horses, expanded in monolayers with FGF-2, and cultured with autogenous acellular pulverized tendon and IGF-I for seven days. Initial cell isolation and subsequent monolayer proliferation were assessed. In the cell: pulverized tendon cultures, cell viability, expression of collagen types I and II, and cartilage oligomeric matrix protein (COMP) mRNAs, collagen and glycosaminoglycans (GAG) syntheses were assessed. Tendon-derived cells proliferated significantly more rapidly in the initial monolayer expansion cultures in comparison to bone marrow-derived cells. Further, monolayer expansion with FGF-2 significantly increased the cell numbers of tendon-derived cells. Expression of collagen type I, collagen type III and COMP mRNAs was higher in tendon-derived cell groups than bone marrow-derived cell groups. However, IGF-I supplementation significantly increased collagen type I and type III mRNA expression in only the bone marrow-derived cell groups. IGF-I supplementation significantly increased collagen synthesis of bone marrow-derived cells. Monolayer expansion with FGF-2 followed by IGF-I supplementation significantly increased proteoglycan synthesis in tendon-derived cells. In summary, tendon-derived cell cultures generated more cells and showed increased matrix synthesis following monolayer expansion with FGF-2 when compared to bone marrow-derived cells. In vivo experiments using FGF-2 expanded tendon-derived cells are warranted to evaluate the effects on tendon healing.
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ABSTRACT: Trotz jüngster technischer Weiterentwicklungen in der Rotatorenmanschetten(RM)-Chirurgie belegen Studien eine persistierend hohe Versagensquote. Biologische Faktoren könnten die Heilung im Bereich der RM-Refixation vielversprechend unterstützen. Die momentane Studienlage ist in Bezug auf die biologische Augmentation von RM-Rekonstruktionen noch sehr lückenhaft. Dabei gilt es, ein optimales Zusammenspiel zwischen den 3 Komponenten Wachstumsfaktoren, den zellulären Anteilen und der extrazellulären Matrix (ECM) zu erreichen. Allerdings gibt es erfolgversprechende, wenn auch häufig bislang erst experimentelle Ansätze, die Knochen-Sehnen-Heilung zu verbessern. Hierdurch lassen sich möglicherweise in Zukunft die klinischen Resultate nach RM-Rekonstruktionen optimieren.Arthroskopie 05/2012; 25(2). DOI:10.1007/s00142-011-0671-y