Biophysical Modulation of Mesenchymal Stem Cell Differentiation in the Context of Skeletal Repair.

A prominent feature of the skeleton is its ability to remodel in response to biophysical stimuli and to repair under varied biophysical conditions. This allows the skeleton considerable adaptation to meet its physiological roles of stability and movement. Skeletal cells and their mesenchymal precursors exist in a native environment rich with biophysical signals, and they sense and respond to those signals to meet organismal demands of the skeleton. While mechanical strain is the most recognized of the skeletal biophysical stimuli, signaling phenomena also include fluid flow, hydrostatic pressure, shear stress, and ion-movement-related electrokinetic phenomena including, prominently, streaming potentials. Because of the complex interactions of these electromechanical signals, it is difficult to isolate the significance of each. The application of external electrical and electromagnetic fields allows an exploration of the effects of these stimuli on cell differentiation and extra-cellular matrix formation in the absence of mechanical strain. This review takes a distinctly translational approach to mechanistic and preclinical studies of differentiation and skeletal lineage commitment of mesenchymal cells under biophysical stimulation. In vitro studies facilitate the examination of isolated cellular responses while in vivo studies permit the observation of cell differentiation and extracellular matrix synthesis.

Deconstructing the Minimum Clinically Important Difference (MCID).

PURPOSE: The minimal clinically important difference (MCID) is a way of dichotomizing data for assessment of success or failure based on clinically meaningful changes. The magnitude of the MCID is often misunderstood to be a singular quantity applicable across studies. However, substantial differences have been reported among MCIDs for the same outcome measures usually based upon differences extrinsic to the calculation. This study explores the effects of variabilities intrinsic to the calculation of the MCID. METHODS: The MCIDs for two knee replacement patient-reported outcomes measures of pain and function were calculated at 1 year postoperative with an integrative anchor and distribution-based method using external anchor questions and receiver operator characteristic (ROC) curves. The effects upon the magnitude and precision of the MCIDs of varying the anchor questions, the thresholds for success/failure, and the sample sizes were examined. RESULTS: Wide variabilities were observed in both the magnitudes and precision of the MCIDs. The threshold for success had the largest effect on magnitude of pain scores, while the sample size had the largest effect on precision. For function scores, the sample size had the largest effect on magnitude, and the anchor question had the largest effect on precision. CONCLUSION: Comparisons among MCIDs are difficult to interpret if elements of the calculations are different and influence the results. While factors extrinsic to the calculations, e.g., study population, trial design, methods of calculation, etc., are known to produce differences in the magnitude of MCIDs, this study shows that more subtle and less obvious factors intrinsic to the calculations have profound effects on both the magnitude and precision of MCIDs. Comparisons among MCIDs should be made with caution and call for greater transparency in reporting intrinsic methods. It is probably advisable for individual studies to calculate their own MCIDs and not rely on published values.

The use of human biospecimens for research.

This discussion presents many of the ethical, legal, and financial issues that underlie the contemporary regulatory framework for research with human biospecimens. Some considerations, such as claims of donor control over their biospecimens, could potentially constrain researchers' freedom of action. We first consider concepts underlying consent to donate biospecimens for research. A requirement to obtain consent for donation of a biospecimen could conceptually be based upon the autonomy of the donor, or on property rights of the donor, or a combination of both concepts. If these concepts affect how consent is implemented, it could have significant downstream consequences for research and researchers. We present elements of the revision of the common rule that affect the use of human biospecimens including the current consent regulations based on transparency and autonomy, and the distinction between consent for, and ownership of, biospecimens. One of the major judicial opinions that denied property rights for biospecimens is described together with some implications for the research community of attributing ownership of biospecimens to their donors. We then consider transactional aspects of biospecimen donation. Considering biospecimens as a negotiable commodity presents both constraints and opportunities for donors and researchers. Compensation for biospecimens can be negotiated under contract law. Allowing donor control of the secondary research use of deidentified biospecimens could have an inhibiting effect on research. If donors possessed such control, even deidentification would not necessarily eliminate their ability to influence future research. Accordingly, new models of biospecimen donation are appearing in which the research community will have a substantial interest.

Pulsed Electromagnetic Field Stimulation of Bone Healing and Joint Preservation: Cellular Mechanisms of Skeletal Response.

The US FDA has approved pulsed electromagnetic fields (PEMFs) as a safe and effective treatment for nonunions of bone. Despite its clinical use, the mechanisms of action of electromagnetic stimulation of the skeleton have been elusive. Recently, cell membrane receptors have been identified as the site of action of PEMF and provide a mechanistic rationale for clinical use. This review highlights key processes in cell responses to PEMF as follows: (1) signal transduction through A2A and A3 adenosine cell membrane receptors and (2) dose-response effects on the synthesis of structural and signaling extracellular matrix (ECM) components. Through these actions, PEMF can increase the structural integrity of bone and cartilage ECM, enhancing repair, and alter the homeostatic balance of signaling cytokines, producing anti-inflammatory effects. PEMFs exert a proanabolic effect on the bone and cartilage matrix and a chondroprotective effect counteracting the catabolic effects of inflammation in the joint environment. Understanding of PEMF membrane targets, and of the specific intracellular pathways involved, culminating in the synthesis of ECM proteins and reduction in inflammatory cytokines, should enhance confidence in the clinical use of PEMF and the identification of clinical conditions likely to be affected by PEMF exposure.