Pegylated insulin-like growth factor-1 biotherapeutic delivery promotes rotator cuff regeneration in a rat model.

Tears in the rotator cuff are challenging to repair because of the complex, hypocellular, hypovascular, and movement-active nature of the tendon and its enthesis. Insulin-like Growth Factor-1 (IGF-1) is a promising therapeutic for this repair. However, its unstable nature, short half-life, and ability to disrupt homeostasis has limited its clinical translation. Pegylation has been shown to improve the stability and sustain IGF-1 levels in the systemic circulation without disrupting homeostasis. To provide localized delivery of IGF-1 in the repaired tendons, we encapsulated pegylated IGF-1 mimic and its controls (unpegylated IGF-1 mimic and recombinant human IGF-1) in polycaprolactone-based matrices and evaluated them in a pre-clinical rodent model of rotator cuff repair. Pegylated-IGF-1 mimic delivery reestablished the characteristic tendon-to-bone enthesis structure and improved tendon tensile properties within 8 weeks of repair compared to controls, signifying the importance of pegylation in this complex tissue regeneration. These results demonstrate a simple and scalable biologic delivery technology alternative to tissue-derived grafts for soft tissue repair.

Kinetic degradation and biocompatibility evaluation of polycaprolactone-based biologics delivery matrices for regenerative engineering of the rotator cuff.

Whereas synthetic biodegradable polymers have been successfully applied for the delivery of biologics in other tissues, the anatomical complexity, poor blood supply, and reduced clearance of degradation byproducts in the rotator cuff create unique design challenges for implantable biomaterials. Here, we investigated lower molecular weight poly-lactic acid co-epsilon-caprolactone (PLA-CL) formulations with varying molecular weight and film casting concentrations as potential matrices for the therapeutic delivery of biologics in the rotator cuff. Matrices were fabricated with target footprint dimensions to facilitate controlled and protected release of model biologic (Bovine Serum Albumin), and anatomically-unhindered implantation under the acromion in a rodent model of acute rotator cuff repair. The matrix obtained from the highest polymeric-film casting concentration showed a controlled release of model biologics payload. The tested matrices rapidly degraded during the initial 4 weeks due to preferential hydrolysis of the lactide-rich regions within the polymer, and subsequently maintained a stable molecular weight due to the emergence of highly-crystalline caprolactone-rich regions. pH evaluation in the interior of the matrix showed minimal change signifying lesser accumulation of acidic degradation byproducts than seen in other bulk-degrading polymers, and maintenance of conformational stability of the model biologic payload. The context-dependent biocompatibility evaluation in a rodent model of acute rotator cuff repair showed matrix remodeling without eliciting excessive inflammatory reaction and is anticipated to completely degrade within 6 months. The engineered PLA-CL matrices offer unique advantages in controlled and protected biologic delivery, non-toxic biodegradation, and biocompatibility overcoming several limitations of commonly-used biodegradable polyesters.

Evaluation of a bioengineered ACL matrix's osteointegration with BMP-2 supplementation.

A poly (l-lactic) acid bioengineered anterior cruciate ligament (ACL) matrix has previously demonstrated the ability to support tissue regeneration in a rabbit ACL reconstruction model. The matrix was designed for optimal bone and ligament regeneration by developing a matrix with differential pore sizes in its bone and ligament compartments. Building upon past success, we designed a new bioengineered ACL matrix that is easier to install and can be used with endobutton fixation during ACL reconstruction. To achieve this, a new braiding procedure was developed to allow the matrix to be folded in half, making two-limbs, while maintaining its bone and ligament compartments. The osteointegration of the matrix with and without bone morphogenetic protein 2 (BMP-2) supplementation was evaluated in a rabbit ACL reconstruction model. Two doses of BMP-2 were evaluated, 1 and 10 µg, and delivered by saline injection into the bone tunnel at the end of surgery. A fibrous matrix-to-bone interface with occasional Sharpey's fibers was the primary mode of osteointegration observed. The matrix was also found to support a fibrocartilage matrix-to-bone interface. In some cases, the presence of chondrocyte-like cells was observed at the aperture of the bone tunnel and the center of the matrix within the bone tunnel. Treatment with BMP-2 was associated with a trend towards smaller bone tunnel cross-sectional areas, and 1 µg of BMP-2 was found to significantly enhance osteoid seam width in comparison with no BMP-2 or 10 µg of BMP-2 treatment. Regenerated tissue was well organized within the bioengineered ACL matrix and aligned with the poly (l-lactic) acid fibers. Disorganized tissue was found between the two-limbs of the bioengineered ACL matrix and hypothesized to be due to a lack of structural scaffolding. This study suggests that the bioengineered ACL matrix can undergo similar modes of osteointegration as current autografts and allografts, and that BMP-2 treatment may enhance osteoblastic activity within the bone tunnels.

Assessment of pronator quadratus repair integrity following volar plate fixation for distal radius fractures: a prospective clinical cohort study.

PURPOSE: To assess prospectively the integrity of pronator quadratus (PQ) muscle repair following volar plate fixation of distal radius fractures and to compare the clinical and radiographic outcomes of durable versus failed repairs in 24 subjects. In addition, by grading the degree of PQ injury, an attempt was made to correlate failure of repair with the PQ injury severity. METHODS: The extent of PQ injury was graded for each fracture. After fracture fixation, the PQ muscle was repaired along its radial and distal borders. Radiopaque hemoclips were attached to each side of the PQ repair, 2 radially and 2 distally. The distance between these markers at time 0 versus x-rays taken at approximately 2 weeks, 6 weeks, and 3 months was recorded. Clip displacement of 1 cm or more compared to time 0 indicated repair failure. RESULTS: One of 24 repairs (4%) failed at 3 months. No statistical difference was noted between the type of PQ injury and wrist flexion/extension, pronation/supination, and grip strength. CONCLUSIONS: Pronator quadratus repairs after volar plate fracture fixation are generally durable. They withstand forces that occur at the distal radius during the healing process with a 4% failure rate. No correlation was shown between type of PQ injury and radiographic failure of the repair.