Stephen B. Milam

Reconstruction of bone using calcium phosphate bone cements: a critical review.

The calcium phosphate cements (CPCs) are rapidly emerging as a new technology in craniofacial surgery and will soon impact many areas of orthopedic and maxillofacial reconstructive surgery as well. These materials are, in many ways, substantially different from the previously marketed dense, crystalline, hydroxyapatite (HA) ceramic materials of the 1980s. The CPCs are blends of amorphous and crystalline calcium phosphate compounds and set to produce HA. These materials 1) have x-ray diffraction spectra similar to the mineral phase of bone, 2) set endothermically at body temperature, 3) are capable of being injected into fractures or bone defects, 4) have compressive strengths equal to or greater than bone, 5) form chemical bonds to the host bone, and 6) may exhibit osteoconductive properties. This review provides an overall commentary on the different types of CPCs, emphasizing those materials currently on the market or soon to emerge in the marketplace.

Pathogenesis of degenerative joint disease in the human temporomandibular joint.

The wide range of disease prevalences reported in epidemiological studies of temporomandibular degenerative joint disease reflects the fact that diagnoses are frequently guided by the presence or absence of non-specific signs and symptoms. Treatment is aimed at alleviating the disease symptoms rather than being guided by an understanding of the underlying disease processes. Much of our current understanding of disease processes in the temporomandibular joint is based on the study of other articular joints. Although it is likely that the molecular basis of pathogenesis is similar to that of other joints, additional study of the temporomandibular joint is required due to its unique structure and function. This review summarizes the unique structural and molecular features of the temporomandibular joint and the epidemiology of degenerative temporomandibular joint disease. As is discussed in this review, recent research has provided a better understanding of the molecular basis of degenerative joint disease processes, including insights into: the regulation of cytokine expression and activation, arachidonic acid metabolism, neural contributions to inflammation, mechanisms of extracellular matrix degradation, modulation of cell adhesion in inflammatory states, and the roles of free radicals and heat shock proteins in degenerative joint disease. Finally, the multiple cellular and molecular mechanisms involved in disease initiation and progression, along with factors that may modify the adaptive capacity of the joint, are presented as the basis for the rational design of new and more effective therapy.

Sexual dimorphism in the distribution of estrogen receptors in the temporomandibular joint complex of the baboon

The localization of radiolabeled estradiol was examined in the temporomandibular complex of male baboons by means of an autoradiographic technique. Five baboons were studied. Four animals received only the tritiated estrogen (1 microgram/kgm) and one animal, which served as the control, received both the tritiated estrogen and the unlabeled estrogen (100 micrograms/kgm). The study failed to demonstrate nuclear uptake and retention of tritiated estrogen in any of the tissues of the temporomandibular joint complex, including the articular surface of the condyle, articular disk, capsule, and muscles of mastication. However, estrogen receptors were identified in other tissues, including the pituitary. All tissues examined in the control animal were negative for estrogen receptors. It was concluded that there were no estrogen receptors in the temporomandibular joint complex of aged male baboons. As in previous studies, these findings provide additional evidence of a sexual dimorphism with respect to estrogen receptor distribution in the temporomandibular joint complex of the baboon. Furthermore, it is reasonable to speculate that estrogens may modulate a variety of metabolic functions in these tissues that could be important in the maintenance, repair, and/or pathogenesis of the temporomandibular joint.

Pathogenesis of degenerative temporomandibular joint arthritides

Over the past decade, remarkable progress has been made in the study of molecular mechanisms involved in degenerative temporomandibular joint arthritides. Based on recent findings, models of degenerative temporomandibular joint disease predict that mechanical loads trigger a cascade of molecular events leading to disease in susceptible individuals. These events involve the production or release of free radicals, cytokines, fatty acid catabolites, neuropeptides, and matrix-degrading enzymes. Under normal circumstances, these molecules may be involved in the remodeling of articular tissues in response to changing functional demands. However, if functional demands exceed the adaptive capacity of the temporomandibular joint or if the affected individual is susceptible to maladaptive responses, then a disease state will ensue. An individual’s susceptibility to degenerative temporomandibular joint disease may be determined by several factors, including genetic backdrop, sex, age, and nutritional status. It is hoped that, by furthering our understanding of the molecular events that underlie degenerative temporomandibular joint diseases, improved diagnostics and effective therapies for these debilitating conditions will be developed.

Cells Transmit Spatial Information by Orienting Collagen Fibers

Parallel orientation of large cell populations occurs when cells are cultured on thin collagen films if and only if a gel is restrained at two or more edges. The direction in which cell bodies orient is determined by the geometry of the gel. It can be shown that tension exerted by cells on a collagen gel leads to reorientation of collagen fibers in a direction determined by the initial geometry of the collagen gel. Hence, tension generated by cells leads to collagen fiber orientation which, in turn, determines the spatial orientation and morphology of cells. Thus, without cell-to-cell contact, cells can communicate with each other by applying tension to collagen fibers in their extracellular matrix. Information concerning the shape of the environment can be transmitted via such long range forces.

Pathophysiology and Pharmacologic Control of Osseous Mandibular Condylar Resorption

PURPOSE When osseous mandibular condylar resorption occurs there can be many different diagnoses: inflammatory arthritis, TMJ compression, trauma, hormone imbalances, and others. While each diagnosis has its own original inciting event, the pathophysiological pathway for articular bone loss is the same. The aim of this article is to review the relevant literature on condylar resorption and the use of pharmacotherapy to control arthritic erosions and resorption. MATERIALS AND METHODS The literature search was performed using PubMed database with various combinations of related keywords. Preference was given to clinical trials when reviewing articles. RESULTS The literature reveals that common cellular level events associated with articular resorption include the activation of osteoblasts by cytokines, free radicals, hormone imbalances and/or potent phospholipid catabolites. The osteoblast then activates the recruitment of osteoclasts and promotes the release of matrix degrading enzymes from the osteoclast. Research into articular erosions has focused on elucidating the important steps in the bone destructive pathways and interfering with them by pharmacological means. The use of antioxidants, tetracyclines, omega-3 fatty acids, non-steroidal anti-inflammatories and inflammatory cytokine inhibitors to aid in preventing and controlling articular bone loss including osseous mandibular condylar resorption has been successful. CONCLUSION By understanding the known pathways that lead to condylar resorption and the individual patients susceptibilities, targeted pharmacotherapy might be able to disturb these pathways and prevent further condylar resorption. Basic clinical investigations and randomized clinical trials are still required, but the present science is encouraging.

Integrins regulate opioid receptor signaling in trigeminal ganglion neurons.

The binding of integrins to the extracellular matrix results in focal organization of the cytoskeleton and the genesis of intracellular signals that regulate vital neuronal functions. Recent evidence suggests that integrins modulate G-protein-coupled receptor (GPCR) signaling in hippocampal neurons. In this study we evaluated the hypothesis that integrins regulate the mu opioid receptor in rat trigeminal ganglion neurons. For these studies, primary cultures of adult rat trigeminal ganglion neurons were used to demonstrate the colocalization of beta1 and beta3 integrins with mu opioid receptor in caveolin-1-rich membrane fractions, and at focal adhesions sites generated by integrin ligand binding. Furthermore, we show that the mu opioid receptor agonist, DAMGO ([D-Ala(2),N-MePhe(4),Gly-ol(5)]enkephalin), inhibits cyclic AMP (cAMP) accumulation in response to prostaglandin E2 (PGE(2)) stimulation in bradykinin-primed, but not unprimed, cultured trigeminal ganglia neurons. Application of soluble GRGDS (Gly-Arg-Gly-Asp-Ser) peptides that bind specific integrins (i.e. RGD-binding integrins) completely abolished the DAMGO effect in bradykinin-primed trigeminal ganglia neurons, but did not alter bradykinin-mediated hydrolysis of phosphatidylinositol. Likewise, monospecific anti-beta1 and anti-beta3 integrin subunit antibodies blocked this DAMGO effect in bradykinin-primed trigeminal ganglia neurons. Indeed, application of anti-beta1 integrin subunit actually reversed DAMGO signaling, resulting in increased cAMP accumulation in these cells. This suggests that the relative amounts of specific activated integrins at focal adhesions may govern signaling by the mu opioid receptor, perhaps by altering interactions with G proteins (e.g. Galphai vs. Galphas). Collectively, these data provide the first evidence that specific integrins regulate opioid receptor signaling in sensory neurons.

Protein interactions with particulate teflon: Implications for the foreign body response

PURPOSE This study examined the nature of protein interactions with particulate polytetrafluoroethylene (PTFE, Teflon) to elucidate possible mechanisms involved in the foreign body response directed against failed Proplast/Teflon implants. MATERIALS AND METHODS Fifty milligrams PTFE prepared to particle sizes ranging from < 32 microns to > 300 microns was incubated with newborn bovine serum. The total amount of protein adsorbed to the PTFE particles was determined using a standard colorimetric assay. The structural and functional integrity of the proteins adsorbed to PTFE was also examined. For these studies, xanthine oxidase was substituted for serum, and the enzymatic activity of xanthine oxidase adsorbed to PTFE was determined. Finally, primary interactions between protein and PTFE particles were assessed in experiments using water, 2 or 8 mol/L urea, 1 mol/L Nacl, or 1% sodium dodecyl sulfate in an attempt to dissociate bound protein from the surfaces of PTFE particles. RESULTS Serum proteins bind almost instantly to the surface of PTFE particles. The effective surface area of PTFE increases dramatically with reduction of the material to small particles, as does the total amount of protein adsorbed by the particulate PTFE. Proteins bind to PTFE principally by hydrophobic interactions, and their three-dimensional structure is significantly perturbed by this interaction. In the case of xanthine oxidase, adsorption to PTFE distorts protein structure to the extent that biologic activity is eliminated. CONCLUSIONS The amount of serum protein adsorbed to PTFE particles varies inversely with particle size for a constant mass of material. It is believed that the foreign body response directed against this material is related to the amount and relative distortion of proteins adsorbed to its surface. If so, it appears that reduction of an implant to small particles (typically 50 micron or less) will dramatically increase the biologic signal to local cell populations. Thus, the severity of the biologic response to PTFE debris may be dependent largely on the size of the debris particles.

17β-Estradiol Rapidly Enhances Bradykinin Signaling in Primary Sensory Neurons In Vitro and In Vivo

Many studies have demonstrated that premenopausal women are at increased risk for various pain disorders. Pain-sensing neurons, termed “nociceptors,” in the trigeminal ganglia (TG) and dorsal root ganglia (DRG) express receptors for inflammatory mediators and noxious physical stimuli and transmit signals for central processing of pain sensation. Estrogen receptors (ERs) are also expressed on nociceptors in the TG and DRG, and there is ample literature to suggest that activation of ERs can influence pain mechanisms. However, the mechanism for ER modulation of nociceptor activity is incompletely understood. The aim of this study was to characterize the effect of 17β-estradiol (17β-E2) on signaling of the inflammatory mediator bradykinin (BK) in primary cultures of rat sensory neurons and a behavioral model of thermal allodynia in rats. Here, we show that exposure to 17β-E2 rapidly (within 15 min) enhanced responses to BK in vitro and in vivo. The 17β-E2-mediated enhancement of BK signaling was not blocked by the transcription inhibitor anisomycin and was mediated by a membrane-associated ER. The effect of 17β-E2 to enhance BK responses required activation of β1-containing, RGD-binding integrins. These data show that 17β-E2 rapidly enhances inflammatory mediator responses both in vitro and in vivo and suggest that 17β-E2 acting at primary sensory pain neurons may participate in regulating the sensitivity of women to painful stimuli.

Detection and preliminary characterization of matrix metalloproteinase activity in temporomandibular joint lavage fluid

In this study, lavage fluid was fractionated from the superior joint space in patients with temporomandibular joint (TMJ) dysfunction. A hide powder azure protease assay was used to assess protease activity in lavage fluid. No correlation between a patients pain and the level of protease activity was demonstrated. Latent as well as active proteases were detected in the sample lavage fluid. Latent matrix metalloproteinases (MMPs) were activated using trypsin. Stromelysin-1 was detected in an active form in lavage fluid by immunozymography. The presence of high molecular weight species with protease activity was also demonstrated. This study validates the presence of stromelysin-1 as well as other MMPs in TMJ lavage fluid and proposes a mechanism for their physiologic activation.