Franklin D. Shuler

Genetic enhancement of matrix synthesis by articular chondrocytes: Comparison of different growth factor genes in the presence and absence of interleukin‐1

OBJECTIVE To determine whether articular chondrocytes express growth factor genes delivered by adenoviral vectors and whether expression of these genes influences matrix synthesis in the presence and absence of interleukin-1 (IL-1). METHODS Monolayer cultures of rabbit articular chondrocytes were infected with recombinant adenovirus carrying genes encoding the following growth factors: insulin-like growth factor 1 (IGF-1), transforming growth factor beta1 (TGFbeta1), and bone morphogenetic protein 2 (BMP-2). As a control, cells were transduced with the lac Z gene. Cultures were also treated with each growth factor supplied as a protein. Levels of gene expression were noted, and the synthesis of proteoglycan, collagen, and noncollagenous proteins was measured by radiolabeling. Collagen was typed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiography. The effects of growth factor gene transfer on proteoglycan synthesis in the presence of IL-1 were also measured. RESULTS The expression of all transgenes was high following adenoviral transduction. Proteoglycan synthesis was stimulated approximately 8-fold by the BMP-2 gene and 2-3-fold by the IGF-1 gene. The effects of BMP-2 and IGF-1 genes were additive upon cotransduction. Synthesis of collagen and noncollagenous proteins, in contrast, was most strongly stimulated by the IGF-1 gene. In each case, collagen typing confirmed the synthesis of type II collagen. IL-1 suppressed proteoglycan synthesis by 50-60%. IGF-1 and TGFbeta genes restored proteoglycan synthesis to control levels in the presence of IL-1. The BMP-2 gene, in contrast, elevated proteoglycan synthesis beyond control levels in the presence of IL-1. CONCLUSION Transfer of growth factor genes to articular chondrocytes can greatly increase matrix synthesis in vitro, even in the presence of the inflammatory cytokine IL-1. This result encourages the further development of gene therapy for the repair of damaged cartilage.

Transfer of LacZ Marker Gene to the Meniscus

BACKGROUND Lesions in the avascular two-thirds of the meniscus do not heal well and are of concern clinically. Various growth factors promote the synthesis of matrix by meniscal cells and thus have the potential to augment healing. However, their clinical application is severely hindered by problems with delivery. An attractive approach to overcoming such problems is to transfer genes that encode the growth factors in question to the site of the injury. As a prelude to this, we evaluated methods for delivering genes to the meniscus. METHODS Gene transfer was evaluated in vitro and in vivo with a lacZ marker gene, which expresses the enzyme beta-galactosidase. Two types of vectors were tested: an adenovirus and a retrovirus. Monolayers of lapine, canine, and human meniscal cells, as well as intact lapine and human menisci, were used for the in vitro studies. Lesions were created in the menisci of rabbits and dogs for the in vivo studies. Gene transfer to the sites of the experimental meniscal lesions in vivo was accomplished in two ways. In the lapine model, a suspension of adenovirus carrying the lacZ marker gene was mixed with whole blood and the clot was inserted into the lesion. In the canine model, retrovirally transduced allogenic meniscal cells carrying the lacZ marker gene were embedded in collagen gels and transferred to the defects. The animals were killed at various time-points, and gene expression was evaluated by histological examination of sections stained with 5-bromo-4-chloro-indolyl-beta-D-galactose (X-gal), from which a blue chromagen is released in the presence of beta-galactosidase. RESULTS Monolayer cultures of lapine, canine, and human meniscal cells were susceptible to genetic transduction by both adenoviral and retroviral vectors. In vitro gene transfer to intact human and lapine menisci proved possible both by direct, adenoviral, delivery and indirect, retroviral, delivery. Gene expression persisted for at least twenty weeks under in vitro conditions. With regard to the in vivo studies, gene expression persisted within the clot and in some of the adjacent meniscal cells for at least three weeks in the lapine defect model. In the canine defect model, gene expression persisted within the transplanted, transduced meniscal cells for at least six weeks. CONCLUSIONS It is possible to transfer genes to sites of meniscal damage and to express them locally within the lesion for several weeks.

WOUND-HEALING RISK FACTORS AFTER OPEN REDUCTION AND INTERNAL FIXATION OF CALCANEAL FRACTURES: Does Correction of Bohler's Angle Alter Outcomes?

The study reviewed in this article evaluated a group of patients who underwent surgical therapy for calcaneal fractures at a Level I trauma center. One group of patients was treated after outpatient referral to the center, whereas the other group was admitted to, and underwent surgery at, the center. This study attempted to determine which patient risk factors or injury characteristics might lead to an increased rate of wound-healing complications. Bohlers angle is a classic radiographic method of determining the severity of calcaneal injury in this group of patients. The question posed by the authors of this study was: Does a drastic correction in Bohlers angle lead to an increased incidence of wound-healing complications? The authors do not recommend undercorrection of Bohlers angle but urge avoidance of overcorrection and stress the importance of early surgical fixation after lateral skin wrinkling is found.

Physicians’ Ability to Manually Detect Isolated Elevations in Leg Intracompartmental Pressure

BACKGROUND Serial physical examination is recommended for patients for whom there is a high index of suspicion for compartment syndrome. This examination is more difficult when performed on an obtunded patient and relies on the sensitivity of manual palpation to detect compartment firmness-a direct manifestation of increased intracompartmental pressure. This study was performed to establish the sensitivity of manual palpation for detecting critical pressure elevations in the leg compartments most frequently involved in clinical compartment syndrome. METHODS Reproducible, sustained elevation of intracompartmental pressure was established in fresh cadaver leg specimens. Pressures tested included 20 and 40 mm Hg (negative controls) and 60 and 80 mm Hg (considered to be consistent with a compartment syndrome). Each leg served as an internal control, with three compartments having a noncritical pressure elevation. Orthopaedic residents and faculty were individually invited to manually palpate the leg with a known compartment pressure and to answer the following questions: (1) Is there a compartment syndrome? (2) In which compartment or compartments do you believe the pressure is elevated, if at all? (3) Describe your examination findings as soft, compressible, or firm. RESULTS When a true-positive result was considered to be the correct detection of an elevation of intracompartmental pressures and correct identification of the compartment with the elevated pressure, the sensitivity of manual palpation was 24%, the specificity was 55%, the positive predictive value was 19%, and the negative predictive value was 63%. With increasing intracompartmental pressure, fasciotomy was recommended with a higher frequency (19% when the pressure was 20 mm Hg, 28% when it was 40 mm Hg, 50% when it was 60 mm Hg, and 60% when it was 80 mm Hg). When a true-positive result of manual palpation was considered to be an appropriate recommendation of fasciotomy, regardless of the ability of the examiner to correctly localize the compartment with the critical pressure elevation, the sensitivity was 54%, the specificity was 76%, the positive predictive value was 70%, and the negative predictive value was 63%. CONCLUSIONS Manual detection of compartment firmness associated with critical elevations in intracompartmental pressure is poor.

Sports Health Benefits of Vitamin D

Context: Vitamin D is a potent secosteroid hormone that provides many skeletal and extraskeletal health benefits. Musculoskeletal injury prevention and recovery are potentially affected by sufficient circulating levels of the storage form of vitamin D: 25-hydroxyvitamin D3, or 25(OH)D. Vitamin D deficiency can exist among young, active, and healthy people, which may put them at increased risk for injury and prolonged recovery. Evidence Aquisition: PubMed was searched using vitamin D and skeletal muscle, vitamin D and athletic performance, and vitamin D review articles. Studies from the 1930s to 2012 were used for the review. Results: There is strong correlation between vitamin D sufficiency and optimal muscle function. Increasing levels of vitamin D reduce inflammation, pain, and myopathy while increasing muscle protein synthesis, ATP concentration, strength, jump height, jump velocity, jump power, exercise capacity, and physical performance. 25(OH)D levels above 40 ng/mL are required for fracture prevention, including stress fractures. Optimal musculoskeletal benefits occur at 25(OH)D levels above the current definition of sufficiency (> 30 ng/mL) with no reported sports health benefits above 50 ng/mL. Conclusions: Vitamin D deficiency is common in athletes. For athletes presenting with stress fractures, musculoskeletal pain, and frequent illness, one should have a heightened awareness of the additional likely diagnosis of vitamin D deficiency. Correction of this deficiency is completed by standardized and supervised oral supplementation protocols producing significant musculoskeletal sports health benefits.

Understanding the burden of osteoporosis and use of the World Health Organization FRAX.

Fracture prevention is a critical component of managing osteoporosis, which is not longer defined by T-score alone. The internationally validated World Health Organization Fracture Risk Assessment Tool (FRAX) provides the clinician a state-of-the-art tool for predicting patients at greatest risk for fracture. The FRAX tool takes into account country, bone mineral density of the hip (when available), age, sex, and 8 clinical risk factors to calculate the 10-year probability of a major osteoporotic fracture and the 10-year probability of a hip fracture. From this tool, an absolute fracture risk is generated, aiding clinicians in determining which patients with low bone mass and osteoporosis to treat.

Rational design of nanofiber scaffolds for orthopedic tissue repair and regeneration

This article reviews recent significant advances in the design of nanofiber scaffolds for orthopedic tissue repair and regeneration. It begins with a brief introduction on the limitations of current approaches for orthopedic tissue repair and regeneration. It then illustrates that rationally designed scaffolds made up of electrospun nanofibers could be a promising solution to overcome the problems that current approaches encounter. The article also discusses the intriguing properties of electrospun nanofibers, including control of composition, structures, orders, alignments and mechanical properties, use as carriers for topical drug and/or gene sustained delivery, and serving as substrates for the regulation of cell behaviors, which could benefit musculoskeletal tissue repair and regeneration. It further highlights a few of the many recent applications of electrospun nanofiber scaffolds in repairing and regenerating various orthopedic tissues. Finally, the article concludes with perspectives on the challenges and future directions for better design, fabrication and utilization of nanofiber scaffolds for orthopedic tissue engineering.

Treatment of Posterior Sternoclavicular Dislocation With Locking Plate Osteosynthesis

Posterior dislocations of the sternoclavicular joint are rare injuries, representing approximately 3% of all major insults to the shoulder girdle. Despite their relative infrequency, they must be diagnosed and treated early because of the proximity of the sternoclavicular joint to sensitive anatomic structures in the superior mediastinum. Physical examination can yield limited findings, and a high index of suspicion is warranted for this injury pattern especially with impingement signs and symptoms: dyspnea, dysphagia, dysphonia, brachial plexus injury, and vascular alterations. Evaluation with plain anteroposterior radiographs is difficult because of superimposed ribs and lungs. A computed tomography scan is required for appropriate evaluation of this injury pattern. Once posterior dislocation of the sternoclavicular joint has been diagnosed, closed reduction should be attempted as soon as possible with a thoracic surgeon available. Most posterior sternoclavicular dislocations can be treated successfully with closed reduction and 6 to 8 weeks of immobilization. Recurrent dislocations or chronic dislocations require open treatment for stabilization. Precisely which technique should be used to obtain stable internal fixation is controversial, but ligament repair with reconstruction appears to be the most widely accepted. This article reports two such cases of recurrent dislocation that were treated with locking plate osteosynthesis as opposed to more commonly used soft tissue stabilization procedures. Both patients experienced a nearly full return to function and are currently doing well. A review of the current literature regarding this subject matter is also included.

Cast-Saw Burns: Evaluation of Skin, Cast, and Blade Temperatures Generated During Cast Removal

BACKGROUND The use of an oscillating saw for cast removal creates a potential for iatrogenic injury and patient discomfort. Burns and abrasions can occur from the heat created by frictional forces and direct blade contact. With use of a cadaver model system, skin temperature measurements were recorded during cast removal with an oscillating saw. METHODS Casts of uniform thickness were applied to cadavers equilibrated to body temperature. The casts were removed by a single individual while simultaneously measuring temperatures at the skin-padding interface, cast-padding interface, and the blade. Variables tested include two removal techniques, two casting materials (fiberglass and plaster), and two cast-padding thicknesses. RESULTS A poor removal technique (the cast saw blade never leaving the cast material during cutting), fiberglass casting material, and thinner cast padding resulted in significantly higher skin temperatures. The poor technique increased skin temperatures by an average of 5.0 degrees C (p < 0.05). Fiberglass casting materials increased skin temperatures by an average of 7.4 degrees C (p < 0.05). Four layers of cast padding compared with two layers decreased skin temperatures by 8.0 degrees C (p < 0.05). CONCLUSIONS The highest skin temperatures were recorded for fiberglass casts with two layers of padding. The lowest skin temperatures were recorded for plaster casts with four layers of padding. Four layers of cast padding compared with two layers significantly reduced skin temperatures for both plaster and fiberglass casts.

Detection of orthopaedic implants by airport metal detectors

Objectives: To report the effect of patients body mass index (BMI), implant type, size, location, number, and material on detection by certified Transportation Security Administration (TSA) and Federal Aviation Administration (FAA) airport metal detectors set to todays standard sensitivity. Design: Retrospective clinical study. Setting: Level 1 university trauma center. Patients: Ninety-six regularly scheduled trauma clinic patients with a wide variety of orthopaedic implants were enrolled in the study from August 2004 through December 2004. Intervention: Patients walked through an airport arch metal detector and were also wanded with a handheld metal detector. Main Outcome Measurements: Detection of implants by arch detector or wand was recorded. We also gathered information regarding BMI, location of implants, type, metal composition, and size. Results: All unilateral prostheses (8/8) and bilateral prostheses (1/1) were detected. Subjects with 4 or fewer screws and no other implants were never detected by the arch metal detector (0/7). For the remaining 78 subjects, the 2 best predictors of detection by the arch were having plates of length >10 holes and having titanium nails (P < 0.001 for each predictor, Walds test for effects in a logistic model). Conclusions: Prostheses, plates of length >10 holes, and titanium nails were the best predictors of detection by the arch. These 3 factors accounted for 42 of the 43 detections by the arch. Body mass index was not shown to affect detectability of orthopaedic implants.