Kathleen A. Derwin

Commercial extracellular matrix scaffolds for rotator cuff tendon repair : Biomechanical, biochemical, and cellular properties

BACKGROUND We are not aware of any in vitro study comparing the biomechanical, biochemical, and cellular properties of commercial extracellular matrix materials marketed for rotator cuff tendon repair. In this study, the properties of GraftJacket, TissueMend, Restore, and CuffPatch were quantified and compared with each other. The elastic moduli were also compared with that of normal canine infraspinatus tendon. METHODS Samples were tested from different manufacturing lots of four materials: GraftJacket (ten lots), TissueMend (six), Restore (ten), and CuffPatch (six). The Kruskal-Wallis test was used to compare thickness, stiffness, and modulus as well as hydroxyproline, chondroitin/dermatan sulfate glycosaminoglycan, hyaluronan, and DNA contents among these matrices. The moduli of the extracellular matrices were also compared with those of normal canine infraspinatus tendon. RESULTS All four extracellular matrices required 10% to 30% stretch before they began to carry substantial load. Their maximum moduli were realized in their linear region at 30% to 80% strain. The elastic moduli of all four commercial matrices were an order of magnitude lower than that of canine infraspinatus tendon. TissueMend had significantly higher DNA content than the other three matrices (p<0.0001), although both Restore and GraftJacket also had measurable amounts of DNA. CONCLUSIONS Our data demonstrate chemical and mechanical differences among the four commercial extracellular matrices that we evaluated. Probably, the source (dermis or small intestine submucosa), species (human, porcine, or bovine), age of the donor (fetal or adult), and processing of these matrices all contribute to the unique biophysical properties of the delivered product. The biochemical composition of commercial extracellular matrices is similar to that of tendon. However, the elastic moduli of these materials are an order of magnitude lower than that of tendon, suggesting a limited mechanical role in augmentation of tendon repair.

Scaffold devices for rotator cuff repair

Rotator cuff tears affect 40% or more of those aged older than 60 years, and repair failure rates of 20% to 70% remain a significant clinical challenge. Hence, there is a need for repair strategies that can augment the repair by mechanically reinforcing it, while at the same time biologically enhancing the intrinsic healing potential of the tendon. Tissue engineering strategies to improve rotator cuff repair healing include the use of scaffolds, growth factors, and cell seeding, or a combination of these approaches. Currently, scaffolds derived from mammalian extracellular matrix, synthetic polymers, and a combination thereof, have been cleared by the U.S. Food and Drug Administration and are marketed as medical devices for rotator cuff repair in humans. Despite the growing clinical use of scaffold devices for rotator cuff repair, there are numerous questions related to their indication, surgical application, safety, mechanism of action, and efficacy that remain to be clarified or addressed. This article reviews the current basic science and clinical understanding of commercially available synthetic and extracellular matrix scaffolds for rotator cuff repair. Our review will emphasize the host response and scaffold remodeling, mechanical and suture-retention properties, and preclinical and clinical studies on the use of these scaffolds for rotator cuff repair. We will discuss the implications of these data on the future directions for use of these scaffolds in tendon repair procedures.

Rotator cuff repair augmentation in a canine model with use of a woven poly-L-lactide device.

BACKGROUND Despite advances in surgical treatment options, failure rates of rotator cuff repair have continued to range from 20% to 90%. Hence, there is a need for new repair strategies that provide effective mechanical reinforcement of rotator cuff repair as well as stimulate and enhance the intrinsic healing potential of the patient. The purpose of this study was to evaluate the extent to which augmentation of acute repair of rotator cuff tendons with a newly designed poly-L-lactide repair device would improve functional and biomechanical outcomes in a canine model. METHODS Eight adult, male mongrel dogs (25 to 30 kg) underwent bilateral shoulder surgery. One shoulder underwent tendon release and repair only, and the other was subjected to release and repair followed by augmentation with the repair device. At twelve weeks, tendon retraction, cross-sectional area, stiffness, and ultimate load of the repair site were measured. Augmented repairs underwent histologic assessment of biocompatibility. In addition, eight pairs of canine cadaver shoulders underwent infraspinatus injury and repair with and without device augmentation with use of identical surgical procedures and served as time-zero biomechanical controls. Eight unpaired, canine cadaver shoulders were included as normal biomechanical controls. RESULTS At time zero, repair augmentation significantly increased the ultimate load (23%) (p = 0.034) but not the stiffness of the canine infraspinatus tendon repair. At twelve weeks, the poly-L-lactide scaffold was observed to be histologically biocompatible, and augmented repairs demonstrated significantly less tendon retraction (p = 0.008) and significantly greater cross-sectional area (137%), stiffness (26%), and ultimate load (35%) than did repairs that had not been augmented (p < 0.001, p = 0.002, and p = 0.009, respectively). CONCLUSIONS While limiting but not eliminating tendon repair retraction, the augmentation device provided a tendon-bone bridge and scaffold for host tissue deposition and ingrowth, resulting in improved biomechanical function of the repair at twelve weeks.

Changes in rotator cuff muscle volume, fat content, and passive mechanics after chronic detachment in a canine model

BACKGROUND Long-standing tears of the rotator cuff can lead to substantial and perhaps irreversible changes in the affected rotator cuff muscles. We developed a chronic rotator cuff tear in a canine model to investigate and quantify the time-related changes in passive mechanics, volume, and fat of the infraspinatus muscle. We hypothesized that infraspinatus muscle stiffness would increase, volume would decrease, and fat content would increase at twelve weeks following tendon detachment. METHODS The right infraspinatus tendon of eight adult mongrel dogs were surgically detached from the proximal part of the humerus. The uninvolved left shoulder served as a control. Muscle volume changes were quantified with use of magnetic resonance imaging. At twelve weeks, the passive mechanical properties of the chronically detached and control muscles were determined intraoperatively with use of a custom-designed device. Intramuscular fat was evaluated histologically at the time that the animals were killed. RESULTS After twelve weeks of detachment, the stiffness was significantly increased in the detached infraspinatus muscles relative to that in the controls (p < 0.0001). Magnetic resonance image analysis demonstrated that the detached muscle volumes decreased by an average of 32% in the first six weeks and remained constant thereafter. Intramuscular fat increased significantly in the detached muscles and to a greater extent in the lateral regions (p < 0.05). CONCLUSIONS The chronically detached muscle is not merely a smaller version of the original muscle but, rather, a different muscle. The detached muscle becomes stiffer, and the passive loads required to repair it can become excessive. A significant reduction in muscle volume occurs within days to weeks following tendon detachment (p < 0.0001). The nonuniformity of changes in muscle fat suggests that fat content should be used cautiously as an indicator of muscle quality.

Improved time-zero biomechanical properties using poly-L-lactic acid graft augmentation in a cadaveric rotator cuff repair model

HYPOTHESIS Rotator cuff repair failure rates range from 20% to 90%, and failure is believed to occur most commonly by sutures cutting through the tendon due to excessive tension at the repair site. This study was designed to determine whether application of a woven poly-L-lactic acid device (X-Repair; Synthasome, San Diego, CA) would improve the mechanical properties of rotator cuff repair in vitro. MATERIALS AND METHODS Eight pairs of human cadaveric shoulders were used to test augmented and non-augmented rotator cuff repairs. Initial stiffness, yield load, ultimate load, and failure mode were compared. RESULTS Yield load was 56% to 92% higher and ultimate load was 56% to 76% higher in augmented repairs. No increase in initial stiffness was found. Failure by sutures cutting through the tendon was reduced, occurring in 17 of 20 non-augmented repairs but only 7 of 20 augmented repairs. CONCLUSIONS Our data show that application of the X-Repair device significantly increased the yield load and ultimate load of rotator cuff repairs in a human cadaveric model and altered the failure mode but did not affect initial repair stiffness.

Oxygen Diffusion Through Natural Extracellular Matrices: Implications for Estimating "Critical Thickness" Values in Tendon Tissue Engineering

Oxygen is necessary for maintaining cell proliferation and viability and extracellular matrix (ECM) production in 3-dimensional tissue engineering. Typically, diffusion is the primary mode for oxygen transport in vitro; thus, ensuring an adequate oxygen supply is essential. In this study, we determined the oxygen diffusion coefficients of 3 natural ECMs that are being investigated as construct scaffolds for tendon tissue engineering: small-intestine submucosa (SIS), human dermis (Alloderm), and canine fascia lata. Diffusion coefficients were determined using a standard diffusion cell system. The ranges for each matrix type were: SIS: 7 x 10(-6) - 2 x 10(-5) cm2/s, Alloderm: 1.9 - 3.1 x 10(-5) cm2/s, and canine fascia lata: 1.6 - 4 x 10(-5) cm2/s. We used the experimental oxygen diffusivity data for these natural ECMs in a mathematical model of oxygen diffusion through a cell-seeded scaffold to estimate the critical size of cell-seeded scaffold that can be cultured in vitro.

Failure With Continuity in Rotator Cuff Repair “Healing”

Background: Ten to seventy percent of rotator cuff repairs form a recurrent defect after surgery. The relationship between retraction of the repaired tendon and formation of a recurrent defect is not well defined. Purpose/Hypotheses: To measure the prevalence, timing, and magnitude of tendon retraction after rotator cuff repair and correlate these outcomes with formation of a full-thickness recurrent tendon defect on magnetic resonance imaging, as well as clinical outcomes. We hypothesized that (1) tendon retraction is a common phenomenon, although not always associated with a recurrent defect; (2) formation of a recurrent tendon defect correlates with the timing of tendon retraction; and (3) clinical outcome correlates with the magnitude of tendon retraction at 52 weeks and the formation of a recurrent tendon defect. Study Design: Case series; Level of evidence, 4. Methods: Fourteen patients underwent arthroscopic rotator cuff repair. Tantalum markers placed within the repaired tendons were used to assess tendon retraction by computed tomography scan at 6, 12, 26, and 52 weeks after operation. Magnetic resonance imaging was performed to assess for recurrent tendon defects. Shoulder function was evaluated using the Penn score, visual analog scale (VAS) score for pain, and isometric scapular-plane abduction strength. Results: All rotator cuff repairs retracted away from their position of initial fixation during the first year after surgery (mean [standard deviation], 16.1 [5.3] mm; range, 5.7-23.2 mm), yet only 30% of patients formed a recurrent defect. Patients who formed a recurrent defect tended to have more tendon retraction during the first 6 weeks after surgery (9.7 [6.0] mm) than those who did not form a defect (4.1 [2.2] mm) (P = .08), but the total magnitude of tendon retraction was not significantly different between patient groups at 52 weeks. There was no significant correlation between the magnitude of tendon retraction and the Penn score (r = 0.01, P = .97) or normalized scapular abduction strength (r = −0.21, P = .58). However, patients who formed a recurrent defect tended to have lower Penn scores at 52 weeks (P = .1). Conclusion: Early tendon retraction, but not the total magnitude, correlates with formation of a recurrent tendon defect and worse clinical outcomes. “Failure with continuity” (tendon retraction without a recurrent defect) appears to be a common phenomenon after rotator cuff repair. These data suggest that repairs should be protected in the early postoperative period and repair strategies should endeavor to mechanically and biologically augment the repair during this critical early period.

Porcine Small Intestine Submucosa as a Flexor Tendon Graft

An attractive strategy for tendon tissue engineering is the use of natural extracellular matrices as scaffold materials. One matrix that has been shown to promote healing and regeneration of neotissue in various applications is porcine-derived small intestinal submucosa. It was the objective of this study to investigate small intestinal submucosa for intrasynovial flexor tendon grafting in a canine model. We hypothesized that at 6 weeks small intestinal submucosa grafts would undergo host cell infiltration, neovascularization, and replacement by host neotendon. We also hypothesized that small intestinal submucosa grafts would be incorporated by the host without extensive adhesions to surrounding tissues and therefore maintain normal digit function. An intrasynovial tendon autograft was used as a gold standard. At 6 weeks the intrasynovial tendon autografts remained viable, contained normal numbers of cells along their length, and had minimal peritendinous adhesions. Four of six autografts had normal function as determined by rotation of the distal interphalangeal joint. Also at 6 weeks, the small intestinal submucosa grafts had host cell infiltration, neovascularization, and wavy, oriented tissue. However, ubiquitous adhesions together with impaired function in all cases suggest that small intestinal submucosa grafts in the configuration used are not suitable as full-length intrasynovial grafts in this tendon and animal model.

Changes in gene expression of individual matrix metalloproteinases differ in response to mechanical unloading of tendon fascicles in explant culture

Immobilization of the tendon and ligament has been shown to result in a rapid and significant decrease in material properties. It has been proposed that tissue degradation leading to tendon rupture or pain in humans may also be linked to mechanical unloading following focal tendon injury. Hence, understanding the remodeling mechanism associated with mechanical unloading has relevance for the human conditions of immobilization (e.g., casting), delayed repair of tendon ruptures, and potentially overuse injuries as well. This is the first study to investigate the time course of gene expression changes associated with tissue harvest and mechanical unloading culture in an explant model. Rat tail tendon fascicles were harvested and placed in culture unloaded for up to 48 h and then evaluated using qRT‐PCR for changes in two anabolic and four catabolic genes at 12 time points. Our data demonstrates that Type I Collagen, Decorin, Cathepsin K, and MMP2 gene expression are relatively insensitive to unloaded culture conditions. However, changes in both MMP3 and MMP13 gene expression are rapid, dramatic, sustained, and changing during at least the first 48 h of unloaded culture. This data will help to further elucidate the mechanism for the loss of mechanical properties associated with mechanical unloading in tendon.

The biomechanical role of scaffolds in augmented rotator cuff tendon repairs.

BACKGROUND Scaffolds continue to be developed and used for rotator cuff repair augmentation; however, the appropriate scaffold material properties and/or surgical application techniques for achieving optimal biomechanical performance remains unknown. The objectives of the study were to simulate a previously validated spring-network model for clinically relevant scenarios to predict: (1) the manner in which changes to components of the repair influence the biomechanical performance of the repair and (2) the percent load carried by the scaffold augmentation component. MATERIALS AND METHODS The models were parametrically varied to simulate clinically relevant scenarios, namely, changes in tendon quality, altered surgical technique(s), and different scaffold designs. The biomechanical performance of the repair constructs and the percent load carried by the scaffold component were evaluated for each of the simulated scenarios. RESULTS The model predicts that the biomechanical performance of a rotator cuff repair can be modestly increased by augmenting the repair with a scaffold that has tendon-like properties. However, engineering a scaffold with supraphysiologic stiffness may not translate into yet stiffer or stronger repairs. Importantly, the mechanical properties of a repair construct appear to be most influenced by the properties of the tendon-to-bone repair. The model suggests that in the clinical setting of a weak tendon-to-bone repair, scaffold augmentation may significantly off-load the repair and largely mitigate the poor construct properties. CONCLUSIONS The model suggests that future efforts in the field of rotator cuff repair augmentation may be directed toward strategies that strengthen the tendon-to-bone repair and/or toward engineering scaffolds with tendon-like mechanical properties.