Christopher T. Chen

Failed Healing of Rotator Cuff Repair Correlates With Altered Collagenase and Gelatinase in Supraspinatus and Subscapularis Tendons

Background: Despite improvements in arthroscopic rotator cuff repair technique and technology, a significant rate of failed tendon healing persists. Improving the biology of rotator cuff repairs may be an important focus to decrease this failure rate. The objective of this study was to determine the mRNA biomarkers and histological characteristics of repaired rotator cuffs that healed or developed persistent defects as determined by postoperative ultrasound. Hypothesis: Increased synovial inflammation and tendon degeneration at the time of surgery are correlated with the failed healing of rotator cuff tendons. Study Design: Case-control study; Level of evidence, 3. Methods: Biopsy specimens from the subscapularis tendon, supraspinatus tendon, glenohumeral synovium, and subacromial bursa of 35 patients undergoing arthroscopic rotator cuff repair were taken at the time of surgery. Expression of proinflammatory cytokines, tissue remodeling genes, and angiogenesis factors was evaluated by quantitative real-time polymerase chain reaction. Histological characteristics of the affected tissue were also assessed. Postoperative (>6 months) ultrasound was used to evaluate the healing of the rotator cuff. General linear modeling with selected mRNA biomarkers was used to predict rotator cuff healing. Results: Thirty patients completed all analyses, of which 7 patients (23%) had failed healing of the rotator cuff. No differences in demographic data were found between the defect and healed groups. American Shoulder and Elbow Surgeons shoulder scores collected at baseline and follow-up showed improvement in both groups, but there was no significant difference between groups. Increased expression of matrix metalloproteinase 1 (MMP-1) and MMP-9 was found in the supraspinatus tendon in the defect group versus the healed group (P = .006 and .02, respectively). Similar upregulation of MMP-9 was also found in the subscapularis tendon of the defect group (P = .001), which was consistent with the loss of collagen organization as determined by histological examination. From a general linear model, the upregulation of MMP-1 and MMP-9 was highly correlated with failed healing of the rotator cuff (R2 = .656). Conclusion: The upregulation of tissue remodeling genes in the torn rotator cuff at the time of surgery provides a snapshot of the biological environment surrounding the torn rotator cuff that is closely related to the healing of repaired rotator cuffs.

Relationship between serum uric acid and bone mineral density in the general population and in rats with experimental hyperuricemia

Higher serum uric acid concentrations have been associated with higher bone mineral density (BMD) in observational studies of older men and perimenopausal or postmenopausal women, prompting speculation of a potential protective effect of uric acid on bone. Whether this relationship is present in the general population has not been examined and there is no data to support causality. We conducted a cross‐sectional analysis of a probability sample of the U.S. population. Demographic data, dietary intake, lifestyle risk factors and physical activity assessment data, serum biochemistry including serum uric acid, and BMD were obtained from 6759 National Health and Nutrition Examination Survey (NHANES; 2005–2010) participants over 30 years of age. In unadjusted analyses, higher serum uric acid levels were associated with higher BMD at the femoral neck, total hip, and lumbar spine in men, premenopausal women, and postmenopausal women not treated with estrogen. However, these associations were no longer statistically significant after adjustment for potential confounders, including age, body mass index (BMI), black race, alcohol consumption, estimated glomerular filtration rate (eGFR), serum alkaline phosphatase, and C‐reactive protein (CRP). This is in contradistinction to some prevailing conclusions in the literature. To further examine the causal effect of higher serum uric acid on skeletal health, including biomechanical properties that are not measurable in humans, we used an established rat model of inducible mild hyperuricemia. There were no differences in BMD, bone volume density, and bone biomechanical properties between hyperuricemic rats and normouricemic control animals. Taken together, our data do not support the hypothesis that higher serum uric acid has protective effects on bone health.

Topographical variations of the strain-dependent zonal properties of tibial articular cartilage by microscopic MRI

Abstract The topographical variations of the zonal properties of canine articular cartilage over the medial tibia were evaluated as the function of external loading by microscopic magnetic resonance imaging (µMRI). T2 and T1 relaxation maps and GAG (glycosaminoglycan) images from a total of 70 specimens were obtained with and without the mechanical loading at 17.6 µm depth resolution. In addition, mechanical modulus and water content were measured from the tissue. For the bulk without loading, the means of T2 at magic angle (43.6 ± 8.1 ms), absolute thickness (907.6 ± 187.9 µm) and water content (63.3 ± 9.3%) on the meniscus-covered area were significantly lower than the means of T2 at magic angle (51.1 ± 8.5 ms), absolute thickness (1251.6 ± 218.4 µm) and water content (73.2 ± 5.6%) on the meniscus-uncovered area. However GAG (86.0 ± 15.3 mg/ml) on the covered area was significantly higher than GAG (70.0 ± 8.8 mg/ml) on the uncovered area. Complex relationships were found in the tissue properties as the function of external loading. The tissue parameters in the superficial zone changed more profoundly than the same properties in the radial zone. The tissue parameters in the meniscus-covered areas changed differently when comparing with the same parameters in the uncovered areas. This project confirms that the load-induced changes in the molecular distribution and structure of cartilage are both depth-dependent and topographically distributed. Such detailed knowledge of the tibial layer could improve the early detection of the subtle softening of the cartilage that will eventually lead to the clinical diseases such as osteoarthritis.

A Comparative Study of Fibronectin Cleavage by MMP-1, -3, -13, and -14

Fibronectin fragments are important for synovial inflammation and the progression of arthritis, and thus, identifying potential enzymatic pathways that generate these fragments is of vital importance. The objective of this study was to determine the cleavage efficiency of fibronectin by matrix metalloproteinases (MMP-1, MMP-3, MMP-13, and MMP-14). Intact human plasma fibronectin was co-incubated with activated MMPs in neutral or acidic pH for up to 24 hours at 37 °C. The size and distribution of fibronectin fragments were determined by Western blot analysis using antibodies that recognized the N-terminals of fibronectin. All MMPs were able to cleave fibronectin at neutral pH. MMP-13 and -14 had the highest efficiency followed by MMP-3 and -1. MMP-3, -13, and -14 generated 70-kDa fragments, a known pro-inflammatory peptide. Further degradation of fibronectin fragments was only found for MMP-13 and -14, generating 52-kDa, 40-kDa, 32-kDa, and 29-kDa fragments. Fibronectin fragments of similar size were also found in the articular cartilage of femoral condyles of normal bovine knee joints. At acidic pH (5.5), the activities of MMP-1 and -14 were nearly abolished, while MMP-3 had a greater efficiency than MMP-13 even though the activities of both MMPs were significantly reduced. These findings suggest that MMP-13 and -14 may play a significant role in the cleavage of fibronectin and the production of fibronectin fragments in normal and arthritic joints.

Posttraumatic Chondrocyte Apoptosis in the Murine Xiphoid

Objective: To demonstrate posttraumatic chondrocyte apoptosis in the murine xiphoid after a crush-type injury and to ultimately determine the pathway (i.e., intrinsic or extrinsic) by which chondrocytes undergo apoptosis in response to mechanical injury. Design: The xiphoids of adult female wild-type mice were injured with the use of a modified Kelly clamp. Postinjury xiphoid cartilage was analyzed via 3 well-described independent means of assessing apoptosis in chondrocytes: hematoxylin and eosin staining, terminal deoxynucleotidyl transferase dUTP nick end labeling assay, and activated caspase-3 staining. Results: Injured specimens contained many chondrocytes with evidence of apoptosis, which is characterized by cell shrinkage, chromatin condensation, nuclear fragmentation, and the liberation of apoptotic bodies. There was a statistically significant increase in the number of chondrocytes undergoing apoptosis in the injured specimens as compared with the uninjured specimens. Conclusions: Chondrocytes can be stimulated to undergo apoptosis as a result of mechanical injury. These experiments involving predominantly cartilaginous murine xiphoid in vivo establish a baseline for future investigations that employ the genetic and therapeutic modulation of chondrocyte apoptosis in response to mechanical injury.

A Biomechanical Analysis of Interference Screw Versus Bone Tunnel Fixation of Flexor Hallucis Longus Tendon Transfers to the Calcaneus

ABSTRACT The flexor hallucis longus tendon transfer is commonly used to restore function in chronic Achilles tendon ruptures and chronic Achilles tendinopathy. The tendon is often secured to the calcaneus either through a bone tunnel or by an interference screw. We hypothesized that tenodesis using the bone tunnel method would be mechanically superior to interference screw fixation for flexor hallucis longus transfers. Eight matched pairs of cadaveric specimens were assigned randomly to the bone tunnel or interference screw technique and were loaded to failure. Biomechanical analysis was performed to evaluate the ultimate strength, peak stress, Youngs modulus, failure strain, and strain energy. Unpaired comparison, paired comparison, and linear regression analyses were used to determine statistical significance. A slight 22% ± 9% decrease in Youngs modulus and a 52% ± 18% increase of strain energy were found in the interference screw group. However, no differences in ultimate strength, peak stress, or failure strain were seen between the 2 groups on paired comparison. Our findings suggest that interference screw fixation provides similar spontaneous biomechanical properties to the use of a bone tunnel for flexor hallucis longus transfer to the calcaneus. The interference screw is a practical option for fixation of the flexor hallucis longus tendon to the calcaneus and can be performed through a single incision approach. &NA; Level of Clinical Evidence: 5

CHAPTER 1:Introduction to Cartilage

Cartilage is a supporting connective tissue that, together with the bone, forms the framework supporting the body as a whole. There are many distinct types of cartilage, which exhibit numerous similarities as well as differences. Among them, articular cartilage is the best known and the most studied type. Articular cartilage is the thin layer of connective tissue that covers the articulating ends of bones in synovial (diarthrodial) joints. It provides a smooth surface for joint movement and acts as a load-bearing medium that protects the bone and distributes stress. The intense interest in articular cartilage is motivated by the critical role its degradation plays in arthritis and related joint diseases, which are the number one cause of disability in humans. This chapter discusses the physical, chemical and cellular properties of cartilage that give the tissue its extraordinary load-bearing characteristics.

Biomechanical Cadaveric Analysis of Biotenodesis Screw Versus Bone Tunnel Fixation Methods in Flexor Hallucis Longus Transfers

The Achilles tendon is the largest tendon in the human body. It connects the gastrosoleus complex to the calcaneus bone in the foot. It thus allows for transfer of force and heel elevation during forward propulsion of the foot in gait. It is also one the most commonly injured tendons. (1). Acute repair or acute intervention for non-operatively treated tendons do well to restore function. However, chronic Achilles tendon ruptures often require tendon transfer rather than attempt at primary repair. The treatment considered the gold standard is the transfer of the flexor hallucis longus (FHL) tendon to the Achilles insertion of the calcaneus (2).Copyright

In Vitro Cartilage Explant Injury Models

Mechanical injury resulting from a single impact or repetitive overloads is the major factor for the onset of post-traumatic arthritis. Researchers have used a variety of explant injury models to study the role of biomechanical factors in cartilage injury in vitro. Although these models cannot emulate all of the events occurring in an injured joint, they allow the evaluation of acute cellular responses and specific degradation mechanisms in well-defined explant culture environment using reproducible loading regimens. This chapter reviews the studies that utilize various loading systems to investigate cartilage injury, and to compare the results in terms of cell death and matrix damage in cartilage. In doing so, the reader will obtain a better understanding of the major biomechanical factors in cartilage injury and how they contribute to post-traumatic arthritis.

NF-κB Mediates Cartilage Degradation Induced by Trauma Injury and Interleukin-1

Chondrocyte death, induced by impact injury (necrosis) and/or apoptotic inducers such as cytokines, and high level of nitric oxide, is important for the development of post-traumatic arthritis (PTA) [1–3]. The upregulation of pro-inflammatory cytokines, such as interleukin −1 (IL-1) and Tumor necrosis factor (TNF) α, is known to mediate cartilage degradation in inflammatory diseases and after trauma injury [1,2, 6–9]. IL-1 induces the degradation of proteoglycan (PG) in cartilage through NF-κB and Mitogen-activated protein kinases (MAPK: p38, ERK and JNK) pathways [1,2,6]. IL-1 is highly upregulated in synovial joint after impact injury, but the role of IL-1 induced chondrocyte death and matrix/PG degradation in injured cartilage is not completely clear.Copyright