The Biological Basis for Surface-dependent Regulation of Osteogenesis and Implant Osseointegration.

Bone marrow stromal cells are regulated by the chemical and physical features of a biomaterial surface. When grown on titanium (Ti) and Ti alloy surfaces, such as titanium-aluminum-vanadium, with specific topographies that mimic the microscale, mesoscale, and nanoscale features of an osteoclast resorption pit, they undergo a rapid change in cell shape to assume a columnar morphology typical of a secretory osteoblast. These cells exhibit markers associated with an osteoblast phenotype, including osteocalcin and osteopontin, and they secrete factors associated with osteogenesis, including bone morphogenetic protein 2, vascular endothelial growth factor, and neurotrophic semaphorins. The pathway involves a shift in integrin expression from α5ß1 to α2ß1 and signaling by Wnt5a rather than Wnt3a. Conditioned media from these cultures can stimulate vasculogenesis by human endothelial cells and osteoblastic differentiation of marrow stromal cells not grown on the biomimetic substrate, suggesting that the surface could promote osteogenesis in vivo through similar mechanisms. In vivo studies using a variety of animal models confirm that implants with biomimetic surfaces result in improved osseointegration compared with Ti implants with smooth surfaces, as do meta-analyses comparing clinical performance of implant surface topographies.

The Value of Phenotypes in Knee Osteoarthritis Research.

BACKGROUND: Over the past decade, phenotypes have been used to help categorize knee osteoarthritis patients relative to being subject to disease, disease progression, and treatment response. A review of potential phenotype selection is now appropriate. The appeal of using phenotypes is that they most rely on simple physical examination, clinically routine imaging, and demographics. The purpose of this review is to describe the panoply of phenotypes that can be potentially used in osteoarthritis research. METHODS: A search of PubMed was used singularly to review the literature on knee osteoarthritis phenotypes. RESULTS: Four phenotype assembly groups were based on physical features and noninvasive imaging. Demographics included metabolic syndrome (dyslipidemia, hypertension, obesity, and diabetes). Mechanical characteristics included joint morphology, alignment, the effect of injury, and past and present history. Associated musculoskeletal disorder characteristics included multiple joint involvement, spine disorders, neuromuscular diseases, and osteoporosis. With the knee as an organ, tissue characteristics were used to focus on synovium, meniscus, articular cartilage, patella fat pad, bone sclerosis, bone cysts, and location of pain. DISCUSSION: Many of these phenotype clusters require further validation studies. There is special emphasis on knee osteoarthritis phenotypes due to its predominance in osteoarthritic disorders and the variety of tissues in that joint. More research will be required to determine the most productive phenotypes for future studies. CONCLUSION: The selection and assignment of phenotypes will take on an increasing role in osteoarthritis research in the future.

Subchondral insufficiency fractures and spontaneous osteonecrosis of the knee may not be related to osteoporosis.

UNLABELLED: The term insufficiency fracture implies inadequate bone and is applied to some subchondral knee magnetic resonance images. We reviewed bone mineral density, body mass index, meniscal extrusion, comorbidities, and demographics in 32 knee insufficiency fracture patients. Only five were osteoporotic. Meniscal extrusion was predominant. PURPOSE: The literature supports systemic osteoporosis as a risk fracture for spontaneous osteonecrosis of the knee (SONK). SONK is also called a subchondral insufficiency fracture. Recognizing that insufficiency fracture and SONK are related, we designed this retrospective study to determine if knee subchondral insufficiency fractures were associated with osteoporosis based on bone mineral density. METHODS: Based on magnetic resonance imaging findings, 32 patients were diagnosed as having an insufficiency fracture by an orthopaedic surgeon with magnetic resonance imaging confirmation by a musculoskeletal radiologist. We reviewed body mass index, age, sex, comorbidities, demographics, and bone mineral density using both T-scores and Z-scores. RESULTS: The average age was 70, and only five patients were osteoporotic. Twenty-six of the 32 patients were female. The average age-related Z-score was 1 standard deviation above normal. CONCLUSIONS: We conclude that osteoporosis is not the underlying cause of this disorder in the majority of patients.

Using hip measures to avoid misdiagnosing early rapid onset osteoarthritis for osteonecrosis.

In the early phases, subchondral insufficiency fractures and rapidly destructive osteoarthritis of the hip are often mistaken for osteonecrosis of the hip. Three hip measures were used comparing combined subchondral insufficiency fractures and rapidly destructive 18 osteoarthritis patients to 18 osteonecrosis patients. Due to the rarity of these conditions there was no statistical power. Initial diagnoses for the osteoarthritis patients were recorded. The osteoarthritis group had significantly higher means for Tönnis angle (P < 0.001), lateral center edge angle (P = 0.006), and acetabular extrusion index (P = 0.014). Only 7 of the 18 patients were initially diagnosed without reservation as subchondral insufficiency fracture or rapidly destructive osteoarthritis. Using hip measures will reduce the misdiagnosis of rapid onset osteoarthritis of the hip for osteonecrosis.

Non-invasive electromagnetic field therapy produces rapid and substantial pain reduction in early knee osteoarthritis: a randomized double-blind pilot study.

This study examined whether a non-thermal, non-invasive, pulsed electromagnetic field (PEMF), known to modulate the calmodulin (CaM)-dependent nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) signaling pathway, could reduce pain in early knee OA. This randomized, placebo-controlled, double-blind pilot clinical study enrolled 34 patients. Patient selection required initial VAS ≥4, 2 h of standing activity per day, and no recent interventions such as cortisone injections or surgery. Results showed VAS pain score decreased in the active cohort by 50 ± 11% versus baseline starting at day 1 and persisting to day 42 (P < 0.001). There was no significant decrease in VAS versus baseline at any time point in the sham cohort (P = 0.227). The overall decrease in mean VAS score for the active cohort was nearly threefold that of the sham cohort (P < 0.001). The results suggest that non-thermal, non-invasive PEMF therapy can have a significant and rapid impact on pain from early knee OA and that larger clinical trials are warranted.

The paths of musculoskeletal scaffold research leading to long-term effects.

BACKGROUND AND PURPOSE: Developing successful musculoskeletal scaffolds for specific tissue replacement has many challenges. Ideal scaffolds support the physiologic needs of the ingrowth tissue until new cells establish a matrix approximating the biomechanical properties of the original tissue or organ construct. Short- and long-term effects on matrix formation and surrounding tissue are critical for clinical applications. METHOD: This is a review of scaffold development of alginate, fibrin, and poly glycolic and polylactic acid scaffolds by three laboratories. RESULTS: Varied chain structures of alginate modified with an RGD-containing peptide sequence (G4RGDY) promotes cell multiplication. Given the proper mix of chain size and radiation used to reduce chain size, the adjusted rate of degradation showed no long-term effect at 21 weeks in vitro. To date, there are no long-term fibrin-based scaffold constructs. Plasmid DNA-laden 75:25 PLGA microspheres were able to have the microsphere incorporated into the polymer solution, resulting in sustained plasmid DNA release for more than 70 days without significant surrounding tissue effects. CONCLUSION: Years of research on the same construct are required before long-term effects of tissue engineering scaffolds can be determined.

Age and BMI variations in bone, muscle, and fat on AP mid-thigh radiographs.

BACKGROUND: Body mass index (BMI) uses height and weight to determine relative fat content. BMI is used in numerous epidemiologic and mechanical studies of hip and knee osteoarthritis (OA). There are more precise, but cumbersome and expensive, measurements of the contribution of body fat to BMI. Our hypotheses were that there would be a large variation in relative mid-thigh bone, muscle, and fat width within specific BMI range and that relative widths change with age and sex. METHODS: The hospital IRB approved a retrospective review of 340 patients who had a recent knee radiograph for knee OA. Using 5.08-cm (2-inch) increments, six groups were created. At height-adjusted reference points on the lower mid-thigh total thigh diameter (TD), muscle diameter (MD), bone diameter (BD), and nonfat diameter (NFD) were measured. Relative widths within BMI groups (<25, 25-30, 30-40, >40) were compared to age and sex. RESULTS: MD, BD, and NFD ratios showed a wide variation in all BMI groups. As would be expected MD, BD, and NFD ratios decreased with increasing BMI. These ratios did not significantly change with age. However, the MD ratio remains similar for each BMI in men, in women it decreases with BMI. CONCLUSION: Adding relative thigh measurements to BMI data could enhance mechanical and epidemiologic studies.

Ethical safeguards for industry-funded research in an academic setting.

The shrinking economy has driven many investigators to seek industrial funding for both clinical and bench research. This has resulted in four concerns for the clinician scientist: (1) research that results in effective clinical application; (2) research design that meets evidence medicine requirements and has clinical significance; (3) adherence to clinical competencies; and (4) research records that are open and reflect both the scientific and economic path to the results of the investigation. This paper reports on how one institution protects the interests of all four stakeholders in any research study in academic centers: the investigator, the institution, patients, and industry. The process makes it possible for the investigator to concentrate on research methodology and to remain secure about the ethical conduct of their research. At our institution, all industrial-funded research is arranged on an institution-to-sponsor basis. Contract language is generated by the institution, not the investigator. This protects the investigator and includes freedom to publish regardless of the results. Issues of intellectual property, patient protection, and the institutions needs, such as intellectual property and compliance with the federal/state guidelines, and indemnification are incorporated into the pre- and post-award applications. Concurrently, Institutional Review Board (IRB) proposals are prepared and submitted. This process leaves a paper trail that provides a transparency acceptable to all stakeholders.

Use of physical forces in bone healing.

During the past two decades, a number of physical modalities have been approved for the management of nonunions and delayed unions. Implantable direct current stimulation is effective in managing established nonunions of the extremities and as an adjuvant in achieving spinal fusion. Pulsed electromagnetic fields and capacitive coupling induce fields through the soft tissue, resulting in low-magnitude voltage and currents at the fracture site. Pulsed electromagnetic fields may be as effective as surgery in managing extremity nonunions. Capacitive coupling appears to be effective both in extremity nonunions and lumbar fusions. Low-intensity ultrasound has been used to speed normal fracture healing and manage delayed unions. It has recently been approved for the management of nonunions. Despite the different mechanisms for stimulating bone healing, all signals result in increased intracellular calcium, thereby leading to bone formation.

Bilateral subchondral cysts without arthroscopic evidence of articular cartilage degradation.

Subchondral cysts in the knee may occur in the progression of osteoarthrosis. We report on bilateral subchondral cysts located in the lateral femoral condyle in an active 39-year-old man presenting with knee pain at rest. Relief was achieved with arthroscopic decompression. Current research and increasing knowledge may help explain this uncommon presentation. Selected cases of this type can benefit from arthroscopic decompression.