Bone grafts,bone substitutes and orthobiologics: The bridge between basic science and clinical advancements in fracture healing

The biology of fracture healing is better understood than ever before, with advancements such as the locking screw leading to more predictable and less eventful osseous healing. However, at times one’s intrinsic biological response, and even concurrent surgical stabilization, is inadequate. In hopes of facilitating osseous union, bone grafts, bone substitutes and orthobiologics are being relied on more than ever before. The osteoinductive, osteoconductive and osteogenic properties of these substrates have been elucidated in the basic science literature and validated in clinical orthopaedic practice. Furthermore, an industry built around these items is more successful and in demand than ever before. This review provides a comprehensive overview of the basic science, clinical utility and economics of bone grafts, bone substitutes and orthobiologics.     

Stimulus-specific effects of endotoxin on superoxide production by rabbit polymorphonuclear leukocytes

The release of superoxide (O2-) by polymorphonuclear leukocytes (PMN) is an important function that contributes to microbial death. Controversy exists as to the effect of bacterial endotoxin (lipopolysaccharide, or LPS) on the production of O2-. We have injected rabbits with 25 micrograms Escherichia coli LPS intravenously and studied PMN function 18 to 24 hours later. Relative to PMN from saline-injected controls, PMN from LPS-treated rabbits released markedly greater amounts of O2- in response to 10 ng/ml phorbol myristate acetate (PMA) as measured by nmol cytochrome C reduced in 20 minutes (40.8 +/- 7.8 for LPS-treated PMN versus 10.1 +/- 1.6 for control, p less than 0.01). LPS injection, however, significantly reduced O2- release in response to C (complement) 5a (1.4 +/- 0.6 nmole/20 minutes for LPS-treated PMN versus 5.6 +/- 1.3 nmole/20 minutes for control, p less than 0.01). O2- release in response to a third stimulus, n-formyl-methionyl-leucyl-phenylalanine (10(-7) to 10(-9) M), was not affected by LPS. O2- release in response to PMA was enhanced over a wide range of PMA concentrations (10 to 300 ng/ml). Kinetic studies over 30 minutes indicated that, after a brief initial latency in measurable response, LPS enhanced responsiveness to PMA at all time points observed. The reduced responsiveness to C5a corresponds to a previously reported down regulation of receptors for this ligand after intravenous LPS. The observations indicate that intravenous LPS can alter a critical function of PMN for at least 24 hours in a stimulus-specific manner.     

Comparative anatomical analysis of human trisomies 13, 18, and 21: I. The forelimb

Human trisomies 13, 18, and 21 exhibit specific neuromuscular phenotypes (Pettersen and Bersu, '82) which include a high proportion of neuromuscular forelimb variations, many of which are atavistic in nature (de Beer, '58; Barash et al., '79; Aziz, '81a). In order to test the neuromuscular phenotype, examine the atavistic nature, and analyze the developmental delay of the trisomy forearm musculature, we dissected the forelimbs of five trisomy 13, ten trisomy 18, and two trisomy 21 cases. Our dissections compare favorably with the existing published trisomy cases (Opitz et al., '79; Pettersen and Bersu, '82). Additionally, we found significant differences in the stage at which developmental arrest occurred in trisomies 13 and 18 for the pectoral complex, extensor digitorum profundus, and intrinsic hand musculature. Some of these muscles, which occur normally in nonhuman primates (Cihak, '67, '69; Dunlap et al., '85), also appear briefly in normal human ontogeny (Cihak, '72), constituting further evidence for developmental delay in aneuploids. The disproportionately effected limb tissues also lend support to the evidence for some degree of autonomy in their development in normal individuals. Our observations are consistent with Shapiro's amplified developmental instability model ('83). Aneuploids may be viewed as genetic variants from which much may be learned about normal limb development, how aneuploidy affects dysmorphogenesis, and the kind of information which exists on the duplicated (or monosomic) chromosome.     

An E mu-v-abl transgene elicits plasmacytomas in concert with an activated myc gene.

To clarify how the v-abl oncogene of Abelson murine leukemia virus contributes to lymphoid tumorigenesis, we introduced the gene linked to an immunoglobulin heavy chain enhancer (E mu) into the mouse germline. Although lymphoid development was not detectably affected in young E mu-v-abl mice, three transgenic lines shared a high predisposition to develop clonal plasmacytomas that secreted IgA or IgG. The unexpected absence of pre-B lymphomas suggests that Abelson virus generates such tumors by infecting an early lymphoid progenitor cell that has not yet activated the heavy chain enhancer. Most plasmacytomas bore a rearranged c-myc gene, apparently as a result of spontaneous translocation to the Igh locus. Moreover, progeny of a cross with analogous E mu-myc mice rapidly developed oligoclonal plasmacytomas. Thus, the collusion of v-abl with c-myc is stage specific, efficiently transforming plasma cells but not pre-B cells or B cells.     

Effect of reduced temperatures and brefeldin A on prolactin secretion and on subcellular distribution of the secretory product and membrane antigens in GH3 pituitary cells.

The effects of reduced temperatures (20, 15 or 10 degrees C) and brefeldin A (BFA) on prolactin (PRL) secretion in the GH3 rat pituitary cell line have been compared. Both treatments inhibit PRL release to different extents. Ultrastructural immunocytochemistry reveals that, depending on the treatment, PRL is blocked at different steps during its intracellular transit. The temperatures of 20 and 15 degrees C block the PRL transport at one face of the Golgi stacks whereas both the temperature of 10 degrees C and BFA treatment induce an arrest of PRL at the level of the rough endoplasmic reticulum (RER) cisternae. Moreover, exposure to 10 degrees C or BFA induces an accumulation of a specific Golgi membrane antigen in the dilated RER structures. However, although disorganized and no longer definable under BFA treatment, the Golgi apparatus remains visible at 10 degrees C. These two last treatments cause also an increase in the number of partly rough, partly smooth tubular structures tentatively called 'paired cisternae'.     

Flagellar regeneration in Chlamydomonas: a model system for studying organelle assembly

How do the many different components of an organelle assemble into a functional structure at an appropriate place and time? Flagellar regeneration by the biflagellate green alga Chlamydomonas is one experimental system in which genetics, biochemistry and ultrastructural analysis are being combined to investigate the assembly of a microtubule-containing organelle. Recent advances in the molecular biology of this 'green yeast' have made possible several new approaches to the problem of flagellar assembly; insights from these new approaches are the focus of this review.     

Persistence of Integrase-Deficient Lentiviral Vectors Correlates with the Induction of STING-Independent CD8+ T Cell Responses

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