rhBMP-12 accelerates healing of rotator cuff repairs in a sheep model.
BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.


CONCLUSIONS
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.
Seeherman
Howard J
HJ
Women's Health and Musculoskeletal Biology, Wyeth Discovery Research, Cambridge, MA 02140, USA. hseeherman@wyeth.com
Archambault
Joanne M
JM
Rodeo
Scott A
SA
Turner
A Simon
AS
Zekas
Lisa
L
D'Augusta
Darren
D
Li
X Jian
XJ
Smith
Erica
E
Wozney
John M
JM
D000818:Animals; D001843:Bone Cements; D019485:Bone Morphogenetic Proteins / Q000008:administration & dosage*; D003094:Collagen; D004195:Disease Models, Animal; D004337:Drug Carriers; D055412:Growth Differentiation Factors; D006820:Hyaluronic Acid; D011994:Recombinant Proteins; D017006:Rotator Cuff; D012756:Sheep; D015503:Surgical Sponges; D013708:Tendon Injuries / Q000601:surgery*; D053656:Tenodesis; D014945:Wound Healing / Q000187:drug effects
D001843:Bone Cements; D019485:Bone Morphogenetic Proteins; D004337:Drug Carriers; C499470:GDF7 protein, human; D055412:Growth Differentiation Factors; D011994:Recombinant Proteins; D006820:Hyaluronic Acid; D003094:Collagen