Stimulation of Rotator Cuff Repair by Sustained Release of Bone Morphogenetic Protein-7 Using a Gelatin Hydrogel Sheet

Abstract

Bone morphogenetic protein-7 (BMP-7) promotes not only osteogenesis but also matrix production in chondrocytes and tenocytes. However, because of its short half-life, maintaining local concentrations of BMP-7 is difficult. We examined the use of a gelatin hydrogel sheet (GHS) for the sustained release of BMP-7 in stimulating rotator cuff repair at the tendon-to-bone insertion. Twelve-week-old male Sprague-Dawley rats were used. Radiolabeled BMP-7 ((125)I-BMP-7) was injected into the subacromial bursa in the (125)I-BMP-7 group, whereas a GHS impregnated with (125)I-BMP-7 was implanted on the tendon attached to the tendon-to-bone insertion in the (125)I-BMP-7+GHS group. Levels of (125)I-BMP-7 in the tendon-to-bone insertion were assessed at 1, 3, 7, 14, and 21 postoperative days. The BMP-7 concentrations were significantly higher in the (125)I-BMP-7+GHS group than in the (125)I-BMP-7 group. Next, the bilateral supraspinatus tendons were resected and sutured to the greater tuberosity of the humerus using the Mason-Allen technique. Treatment groups were created as follows: either phosphate-buffered saline (PBS) or BMP-7 was injected into the subacromial bursa in the PBS and BMP-7 groups, whereas a GHS impregnated with either PBS or BMP-7 was implanted on the repaired tendon attached to the tendon-to-bone insertion in the PBS+GHS and BMP-7+GHS groups. The resected specimens were stained at 2, 4, and 8 postoperative weeks with hematoxylin and eosin as well as Safranin O, and tissue repair was evaluated histologically by using the tendon-to-bone maturing score. Tissue repair was assessed biomechanically at 4 and 8 postoperative weeks. The BMP-7+GHS group at 8 postoperative weeks demonstrated a favorable cartilage matrix production and tendon orientation; moreover, the tendon-to-bone maturing score and the ultimate force-to-failure were the highest in this group. The ability of GHS to provide controlled release of various growth factors has been previously reported. We confirmed that the GHS releases BMP-7 in a sustained manner in the rat shoulder joint. At 8 postoperative weeks, the repaired tissue was mostly restored, both histologically and biomechanically, in the BMP-7+GHS group. We therefore conclude that the sustained release of BMP-7 from a GHS can stimulate rotator cuff repair.

Biologics and stem cell‐based therapies for rotator cuff repair

“…59,73 However, biomechanics were not significantly improved relative to controls. 73 These limited outcomes suggest that additional research will be required to determine whether these chondrogenic/osteogenic BMPs have therapeutic value.…”

“…Of this group, only BMP2 and BMP7 have been tested in the context of rat rotator cuff healing. Although BMP2 delivery via transduced stem cells dramatically impaired healing (as evidenced by reduced mechanical properties and loss of bone), sustained delivery of BMP7 enhanced fibrocartilage deposition at the tendon‐to‐bone site . However, biomechanics were not significantly improved relative to controls .…”

“…Although BMP2 delivery via transduced stem cells dramatically impaired healing (as evidenced by reduced mechanical properties and loss of bone), sustained delivery of BMP7 enhanced fibrocartilage deposition at the tendon‐to‐bone site . However, biomechanics were not significantly improved relative to controls . These limited outcomes suggest that additional research will be required to determine whether these chondrogenic/osteogenic BMPs have therapeutic value.…”

Advances in biologic augmentation for rotator cuff repair

“…In the PDGF‐BB–loaded hydrogel condition, greater collagen fiber orientation, ultimate failure loads, stiffness, and stress to failure were observed at 12 weeks compared with the PBS‐loaded hydrogel control conditions. In another study, Kabuto et al . examined the effect of loading a gelatin hydrogel scaffold with BMP‐7, which is known to promote osteogenesis and matrix production in chondrocytes and tenocytes.…”

“…In the PDGF-BB-loaded hydrogel condition, greater collagen fiber orientation, ultimate failure loads, stiffness, and stress to failure were observed at 12 weeks compared with the PBS-loaded hydrogel control conditions. In another study, Kabuto et al 108 examined the effect of loading a gelatin hydrogel scaffold with BMP-7, which is known to promote osteogenesis and matrix production in chondrocytes and tenocytes. The BMP-7-loaded hydrogels were augmented, via direct injection, in 12-week-old male Sprague-Dawley rat rotator cuff models, and the results indicated that BMP-7 hydrogel conditions enhanced cartilage matrix production and tendon orientation.…”