Roy K. Aaron

Treatment of nonunions with electric and electromagnetic fields.

Electric and electromagnetic fields are, collectively, one form of biophysical technique which regulate extracellular matrix (ECM) synthesis and may be useful in clinically stimulating repair of fractures and nonunions. Preclinical studies have shown that electric and electromagnetic fields regulate proteoglycan (PG) and collagen synthesis in models of endochondral ossification, and increase bone formation in vivo and in vitro. A substantial number of clinical studies have been done that suggest acceleration of bone formation and healing, particularly osteotomies and spine fusions, by electric and electromagnetic fields. Many of these studies have used randomized, placebo controlled designs. In osteotomy trials, greater bone density, trabecular maturation, and radiographic healing were observed in actively treated, compared with placebo-treated patients. In spine fusions, average union rates of 80% to 90% were observed in actively treated patients across numerous studies compared with 65% to 75% in placebo-treated patients. Uncontrolled, longitudinal cohort studies of delayed and nonunions report mean union rates of approximately 75% to 85% in fractures previously refractory to healing. The few randomized controlled studies in delayed and nonunions suggest improved results with electric and electromagnetic fields compared with placebo treatment, and equivalent to bone grafts.

Stimulation of growth factor synthesis by electric and electromagnetic fields.

Biophysical input, including electric and electromagnetic fields, regulate the expression of genes in connective tissue cells for structural extracellular matrix (ECM) proteins resulting in an increase in cartilage and bone production. In in vivo models and clinical situations, this can be manifested as enhanced repair and a gain in mechanical properties of the repairing tissues. The mechanisms by which cell functions are regulated by biophysical input is the subject of this review. Biophysical interactions of electric and electromagnetic fields at the cell membrane are not well understood and require considerable additional study. We review information on transmembrane signaling, channel activation and receptor stimulation or blockade. Understanding physical interactions and transmembrane signaling will most likely be necessary to establish dosing paradigms and improve therapeutic efficacy. Considerable information has been generated on an intermediary mechanism of activity - growth factor stimulation. Electric and electromagnetic fields increase gene expression for, and synthesis of, growth factors and this may function to amplify field effects through autocrine and paracrine signaling. Electric and electromagnetic fields can produce a sustained upregulation of growth factors, which enhance, but do not disorganize endochondral bone formation. Progress in the areas of signal transduction and growth factor synthesis is very rapid and future directions are suggested.

Survival Analysis of Hips Treated with Core Decompression or Vascularized Fibular Grafting Because of Avascular Necrosis

Avascular necrosis of the femoral head is a multifaceted process that leads to articular incongruity and subsequent osteoarthrosis of the joint. Clinicians concur that primary treatment should focus on preservation of the natural surface of the joint; however, there has not been a consensus on how best to accomplish this. While a number of therapeutic interventions have been reported, the efficacy has varied markedly and there have been few statistical comparisons. The purpose of the current study was to use statistical analysis to compare the results of two widely used procedures, vascularized fibular grafting (614 hips; 480 patients) and core decompression (ninety-eight hips; seventy-two patients), for the treatment of avascular necrosis. The patients were stratified according to age and the stage of disease, and a survival analysis was performed with total hip arthroplasty as the end point for failure. None of the eleven hips that had Ficat stage-I disease needed a total joint replacement after being treated with either regimen. Analysis of the hips that had stage-II disease revealed rates of survival, at fifty months, of 65 per cent (twenty-eight of forty-three hips) after core decompression and 89 per cent (ninety-nine of 111 hips) after vascularized fibular grafting. For the hips that had Ficat stage-III disease, the rates of survival at fifty months were 21 per cent (ten of forty-seven hips) after core decompression and 81 per cent (405 of 500 hips) after vascularized fibular grafting. Among the hips that had Ficat stage-II or III disease, the rate of eventual total joint arthroplasty after vascularized fibular grafting was significantly lower than that after core decompression (p < 0.0001). The results indicate that the increased morbidity associated with vascularized fibular grafting is justified by the associated delay in or prevention of articular collapse in hips that have stage-II or III disease.

Sequential release of bioactive IGF-I and TGF-β1 from PLGA microsphere-based scaffolds

Growth factors have become an important component for tissue engineering and regenerative medicine. Insulin-like growth factor-I (IGF-I) and transforming growth factor-beta1 (TGF-beta 1) in particular have great significance in cartilage tissue engineering. Here, we describe sequential release of IGF-I and TGF-beta 1 from modular designed poly(l,d-lactic-co-glycolic acid) (PLGA) scaffolds. Growth factors were encapsulated in PLGA microspheres using spontaneous emulsion, and in vitro release kinetics was characterized by ELISA. Incorporating BSA in the IGF-I formulations decreased the initial burst from 80% to 20%, while using uncapped PLGA rather than capped decreased the initial burst of TGF-beta 1 from 60% to 0% upon hydration. The bioactivity of released IGF-I and TGF-beta 1 was determined using MCF-7 proliferation assay and HT-2 inhibition assay, respectively. Both growth factors were released for up to 70 days in bioactive form. Scaffolds were fabricated by fusing bioactive IGF-I and TGF-beta 1 microspheres with dichloromethane vapor. Three scaffolds with tailored release kinetics were fabricated: IGF-I and TGF-beta 1 released continuously, TGF-beta 1 with IGF-I released sequentially after 10 days, and IGF-I with TGF-beta 1 released sequentially after 7 days. Scaffold swelling and degradation were characterized, indicating a peak swelling ratio of 4 after 7 days of incubation and showing 50% mass loss after 28 days, both consistent with scaffold release kinetics. The ability of these scaffolds to release IGF-I and TGF-beta 1 sequentially makes them very useful for cartilage tissue engineering applications.

The conservative treatment of osteonecrosis of the femoral head. A comparison of core decompression and pulsing electromagnetic fields.

Once roentgenographic changes are apparent, osteonecrosis of the femoral head in the adult generally progresses to osteoarthritis within two to three years. A variety of conservative surgical procedures have been devised to conserve the femoral head with varying success. This study examines the effectiveness of pulsing electromagnetic fields and core decompression in the treatment of osteonecrosis of the femoral head. Both techniques reduce the incidence of clinical and roentgenographic progression. Exposure to pulsing electromagnetic fields appears to be more effective in hips with Ficat II lesions than in hips with more advanced lesions.

Low frequency EMF regulates chondrocyte differentiation and expression of matrix proteins

This study describes the enhancement of chondrogenic differentiation in endochondral ossification by extremely low frequency pulsed electric/magnetic fields (EMFs). The demineralized bone matrix (DBM)‐induced endochondral ossification model was used to examine the effects of EMF stimulation. [35S]‐Sulfate and [3H]‐thymidine incorporation and glycosaminoglycan (GAG) content were determined by standard methods. Proteoglycan (PG) and GAG molecular size and composition were determined by gel chromatography and sequential enzyme digestion. Immunohistochemical and Western blot analysis of PGs were done with antibodies 2B6, 3B3, 2D3 and 5D4. Northern analysis of total RNA extracts was performed for aggrecan, and type II collagen. All data was compared for significance by Students t‐ or analysis of variance (ANOVA)‐tests.

Osteonecrosis of the Hip: Management in the Twenty-first Century

Osteonecrosis, also known as avascular necrosis or aseptic necrosis, is a disease of impaired osseous blood flow. The term aseptic necrosis had been commonly used in the past to distinguish osteonecrosis related to nonseptic causes from that related to septic causes. It commonly affects patients in the third, fourth, or fifth decade of life. Three hundred thousand to six hundred thousand people have osteonecrosis of the femoral head in the United States. The development of osteonecrosis can have a major impact on an individuals lifestyle. Since so many of the patients are young when they are diagnosed, they often need to alter their work and leisure activities. The ultimate goal of treating osteonecrosis of the hip is preservation of the femoral head. However, this is difficult since the condition is associated with a number of different diseases and neither the etiology nor the natural history has been definitively determined. The diagnosis of osteonecrosis accounts for 5% to 12% of total hip replacements performed1. It is difficult to obtain an understanding of the etiologic factors in osteonecrosis because the clinical composition of medical centers varies widely and because, for the most part, reported etiologic associations are based not on prospective studies but rather on cross-sectional and case-control studies. Osteonecrosis can be associated with traumatic or nontraumatic conditions. Since osteonecrosis eventually develops in only a relatively small percentage of patients with any of these conditions2, recent attention has been focused on understanding underlying predispositions to the development of osteonecrosis when challenged by environmental factors. Current interest is centering on genetic mutations leading to hypercoagulability, which results in microthrombosis and osteonecrosis when challenged by environmental (epigenetic) events. Patients with so-called idiopathic osteonecrosis most likely have some type of coagulation abnormality that has not been identified. ### Traumatic Osteonecrosis Osteonecrosis of the femoral …

Supracondylar fracture of the femur after total knee arthroplasty.

In a review of 250 total knee arthroplasties, five patients with rheumatoid arthritis incurred supracondylar fractures of the femur. These fractures may be associated with a surgical encroachment of the anterior femoral cortex during resection of the patellar trochlea. Forty-two percent of patients with excessively deep resections of the patellar trochlea suffered fractures. No fractures occurred in patients without encroachment of the anterior femoral cortex. All patients with fractures also had significant osteoporosis, which may have predisposed them to fracture. A resection of the patellar trochlea that is made too deeply would interrupt the transmission of stresses through the cancellous bony trabeculae of the anterior femoral cortex and could predispose to fracture.

Arthroscopic débridement for osteoarthritis of the knee.

BACKGROUND The role of arthroscopic débridement in the treatment of osteoarthritis of the knee remains to be defined, and few clinical and radiographic characteristics have been quantitatively associated with the outcome. The hypothesis of this study was that the outcome of arthroscopic débridement for osteoarthritis of the knee is associated with preoperative clinical and radiographic features and intraoperative characteristics and that there are subsets of patients who are more and less likely to respond favorably to the treatment. METHODS We performed a cross-sectional study of a consecutive cohort of 122 patients who underwent arthroscopic débridement for the treatment of osteoarthritis of the knee that had been unresponsive to anti-inflammatory therapy. One hundred and ten patients were followed for a mean of thirty-four months. Pain was assessed with the pain domain of the Knee Society scoring system. Radiographs were scored with the Kellgren-Lawrence method, and limb alignment and the widths of the medial and lateral joint spaces were measured. The severity of cartilage lesions was scored intraoperatively with a modified Noyes grading system. Specific methods of data collection and analysis were incorporated to minimize bias. RESULTS Fifty-two (90%) of fifty-eight knees with mild arthritis, normal alignment, and a joint space width of > or = 3 mm were improved after arthroscopic débridement. Conversely, only five (25%) of twenty knees with severe arthritis, limb malalignment, and a joint space width of < 2 mm had substantial relief of symptoms. Of seventy-two patients who had improvement, forty-four (61%) had it within six months after the arthroscopy. The severity of the lesion was highly predictive of the clinical outcome both in patients with mild arthritis and in those with severe arthritis. CONCLUSIONS The severity of the arthritis, as assessed preoperatively with radiography and intraoperatively by rating the severity of cartilage lesions, influences the clinical outcome of arthroscopic débridement of an osteoarthritic knee. Knees with severe arthritis fare poorly, whereas those with mild arthritis fare well. We could not predict the outcome for knees with moderate arthritis. We believe that these observations are relevant for establishing indications for arthroscopy in patients with osteoarthritis of the knee and may be useful for designing studies with a more rigorous experimental design.

Clinical Biophysics: The Promotion of Skeletal Repair by Physical Forces

Abstract:  Skeletal tissues respond to the physical demands of their environment by altering the synthesis and organization of the extracellular matrix. These observations have major implications for how physical environmental demands result in the clinical observations of atrophy and hypertrophy, and how manipulation of the physical environment can be used therapeutically to stimulate repair. Electrical stimulation will be considered as a paradigm of how musculoskeletal tissues respond to physical stimuli. A model of demineralized bone matrix‐induced endochondral ossification has been used because it epitomizes the cell biology of endochondral bone formation in a temporally consistent way. We have studied cartilage and bone matrix production, the temporal locus of cell responsiveness, signal dosimetry, and the synthesis of signaling cytokines (TGF‐β) using biochemical, immunohistochemical, and molecular techniques. Exposure to certain electrical environments enhances chondrocyte differentiation reflected as a temporal acceleration and quantitative increase of cartilage extracellular matrix, earlier onset of osteogenesis, and more mature trabecular bone. The cell pool competent to respond resides in the mesenchymal stage. The enhancement in chondrogenesis is associated with an increase in TGF‐β synthesis mediated at least in part by binding of the transcription factor AP‐1 and may be modulated specifically by phosphorylation of JNK. The clinical practice of orthopedics has empirically created a variety of biophysical environments in attempts to optimize skeletal repair. We are beginning to understand the biological effects of biophysical stimulation and are now poised to replace empiricism with treatment paradigms based upon physiologic understandings of dose and biologic response.