神经生长因子与骨折愈合

神经生长因子主要由来源于神经嵴的神经元支配的靶组织产生,其被这些神经元轴突摄取后逆行运输至胞体,通过多种途径调节神经细胞的基因转录而发挥生物效应,维持神经元的存活、刺激轴突的生长.并对外周神经的发育、营养起重要的作用.在骨组织和骨折骨痴中均可见神经生长因子及其受体的表达,神经生长因子主要是通过促进骨折部位神经的再生参与骨折修复.骨折愈合的机制十分复杂,神经生长因子对骨组织的作用也是多方面、多层次和相互交叉的,其机制尚未完全明确.虽然神经生长因子促进骨折修复作用机制的研究已经取得一些进展,但仍处于初级阶段,其作用机制仍不明确.     

Connecting biology and mechanics in fracture healing: an integrated mathematical modeling framework for the study of nonunions

Both mechanical and biological factors play an important role in normal as well as impaired fracture healing. This study aims to provide a mathematical framework in which both regulatory mechanisms are included. Mechanics and biology are coupled by making certain parameters of a previously established bioregulatory model dependent on local mechanical stimuli. To illustrate the potential added value of such a framework, this coupled model was applied to investigate whether local mechanical stimuli influencing only the angiogenic process can explain normal healing as well as overload-induced nonunion development. Simulation results showed that mechanics acting directly on angiogenesis alone was not able to predict the formation of overload-induced nonunions. However, the direct action of mechanics on both angiogenesis and osteogenesis was able to predict overload-induced nonunion formation, confirming the hypotheses of several experimental studies investigating the interconnection between angiogenesis and osteogenesis. This study shows that mathematical models can assist in testing hypothesis on the nature of the interaction between biology and mechanics.     

A mathematical model to study the effects of drugs administration on tumor growth dynamics

A mathematical model for describing the cancer growth dynamics in response to anticancer agents administration in xenograft models is discussed. The model consists of a system of ordinary differential equations involving five parameters (three for describing the untreated growth and two for describing the drug action). Tumor growth in untreated animals is modelled by an exponential growth followed by a linear growth. In treated animals, tumor growth rate is decreased by an additional factor proportional to both drug concentration and proliferating cells. The mathematical analysis conducted in this paper highlights several interesting properties of this tumor growth model. It suggests also effective strategies to design in vivo experiments in animals with potential saving of time and resources. For example, the drug concentration threshold for the tumor eradication, the delay between drug administration and tumor regression, and a time index that measures the efficacy of a treatment are derived and discussed. The model has already been employed in several drug discovery projects. Its application on a data set coming from one of these projects is discussed in this paper.     

Calcitonin effects on cartilage and fracture healing

The literature about the effects of systemically administered calcitonin on fracture healing and in the prevention of disuse osteoporosis after fracture are reviewed in this study. Fracture healing is a biological process of great importance for the survival of the injured animal. Endochondral ossification is augmented in the fracture site followed by fast remodeling of the produced woven bone. There is strong evidence of the direct effects of calcitonin on cartilage proliferation as well as the vascularization of the callus. Calcitonin is found to promote the cartilaginous phase of fracture healing. On the other hand, the innervation of callus reveals an extensive distribution of sensory fibers containing a calcitonin gene-related peptide, a neuropeptide with potent vasodilatory actions. From several experimental studies, salmon calcitonin administration has been found to have a beneficial effect on fracture healing. Studies in humans also concur that calcitonin may speed up the time of fracture repair and facilitate early mobilization of the injured limb. Finally, calcitonin prevents post-fracture bone loss due to increased post-injury remodeling and lowers hydroxyproline and calcium excretion of patients who underwent internal fixation of fracture on the hip.     

Keratinocyte growth factor signalling: a mathematical model of dermal-epidermal interaction in epidermal wound healing

A wealth of growth factors are known to regulate the various cell functions involved in the repair process. An understanding of their therapeutic value is essential to achieve improved wound healing. Keratinocyte growth factor (KGF) seems to have a unique role as a mediator of mesenchymal-epithelial interactions: it originates from mesenchymal cells, yet acts exclusively on epithelial cells. In this paper, we study KGF's role in epidermal wound healing, since its production is substantially up-regulated after injury. We begin by modelling the dermal-epidermal signalling mechanism of KGF to investigate how this extra production affects the signal range. We then incorporate the effect of KGF on cell proliferation, and using travelling wave analysis we obtain an approximation for the rate of healing. Our modelling shows that the large up-regulation of KGF post-wounding extends the KGF signal range but is above optimal for the rate of wound closure. We predict that other functions of KGF may be more important than its role as a mitogen for the healing process.     

A mathematical framework for the study of morphogenetic development in the slime mold

A mathematical continuum model of the slime mold Dictyostelium discoideum in the morphogenetic development stage is presented, which represents the amoebae as a fluid with surface tension, acted upon by a body force due to the presence of a chemical attractant. Assuming that the amoebae at a given time are in quasi-equilibrium, and that the shape of the organism is prescribed, it is possible to calculate from the model plausible concentration and source-sink distributions that are consistent with the given shape. Typical observed shapes are accounted for by the presence of very large concentrations and concentration gradients of the chemical attractant at the top of the structure.     

A mathematical study of organism growth as an approach to the cancer problem

A mathematical expression is described giving the growth rate of a tissue region as a function of the determining biological factors. It is observed that within the limitations of prediction of this expression, a change of growth to the neoplastic type can be expected under certain conditions of the variables. The growth equations used here are different from others usually mentioned in that they attend to both the positive and the negative growth phases occurring in the course of organism development. The expression derived enables the prediction of an increase in incidence of cancer with age, predicts a decrease in the rate of tumor growth with increasing age, and permits an hypothesis to be made as to the nature of the action of carcinogenic agencies.     

Bacterial colonization and healing of gastric ulcers: the effects of epidermal growth factor

Experimental gastric ulcers are rapidly colonized by various bacteria, resulting in significantly impaired healing. Epidermal growth factor (EGF) is capable of preventing bacterial colonization of the healthy intestinal mucosa. In this study, we examined the possibility that EGF accelerates gastric ulcer healing by reducing bacterial colonization of the ulcer. Gastric ulcers were induced by serosal application of acetic acid. The effect of daily administration of EGF on ulcer healing and bacterial colonization was assessed and compared with the effect of daily treatment with broad-spectrum antibiotics. EGF administration reduced colonization levels and accelerated ulcer healing as effectively as the antibiotic treatment. EGF was without effect on acid secretion or neutrophil infiltration into the ulcer. Bacterial growth was not inhibited in the presence of EGF in vitro. These results demonstrate that EGF reduces bacterial colonization during an established infection of a compromised mucosal surface. This effect may contribute to the ability of EGF to accelerate gastric ulcer healing. This effect is acid independent and not due to an anti-inflammatory effect or to direct bactericidal actions.     

Study of thermal effects of ultrasound stimulation on fracture healing

Low intensity ultrasound stimulation has been used as a strategy to promote fracture healing. This study investigated the mechanism of ultrasound stimulation in enhancing fracture healing. Forty-five adult New Zealand White rabbits were divided into control, microwave treated, and ultrasound stimulation groups. After anesthesia, transverse osteotomy was created at midportion of the fibula bone. Intravital staining followed by fluorescence microscopic examination of new bone formation in the osteotomy site and biomechanical tests on torsional stiffness of the osteotomy site were performed. The difference between each examination was evaluated and analyzed. After ultrasound stimulation, new bone formation in the osteotomy site of the stimulated limb was 23.1-35.8% faster than that of the sham treated limb; the torsional stiffness of the stimulated limb was 44.4-80.0% higher than that of the sham treated limb. In the group of microwave hyperthermia treatment, the new bone formation was higher than that of the sham treated limb, but the difference was not statistically significant. The difference in torsional stiffness between the microwave hyperthermia treated limbs and the sham treated limb was not quite statistically significant. We demonstrated that low intensity ultrasound stimulation could increase the new bone formation and torsional stiffness. These effects probably are not mediated via hyperthermia.     

SUMOylation of the hepatoma-derived growth factor negatively influences its binding to chromatin

Hepatoma-derived growth factor is a nuclear targeted mitogen containing a PWWP domain that mediates binding to DNA. To date, almost nothing is known about the molecular mechanisms of the functions of hepatoma-derived growth factor, its routes of secretion and internalization or post-translational modifications. In the present study, we show for the first time that hepatoma-derived growth factor is modified by the covalent attachment of small ubiquitin-related modifier 1 (SUMO-1), a post-translational modification with regulatory functions for an increasing number of proteins. Using a basal SUMOylation system in Escherichia coli followed by a MALDI-TOF-MS based peptide analysis, we identified the lysine residue SUMOylated located in the N-terminal part of the protein adjacent to the PWWP domain. Surprisingly, this lysine residue is not part of the consensus motif described for SUMOylation. With a series of hepatoma-derived growth factor mutants, we then confirmed that this unusual location is also used in mammalian cells and that SUMOylation of hepatoma-derived growth factor takes place in the nucleus. Finally, we demonstrate that SUMOylated hepatoma-derived growth factor is not binding to chromatin, in contrast to its unSUMOylated form. These observations potentially provide new perspectives for a better understanding of the functions of hepatoma-derived growth factor.     

A mathematical study of a two-regional population growth model

The paper provides a mathematical study of a model of urban dynamics, adjusting to an ecological model proposed by Lotka and Volterra. The model is a system of two first-order non-linear ordinary differential equations. The study proposed here completes the original proof by using the main tools such as a Lyapunov function.     

A numerical approach to the biomechanical analysis of bone fracture healing

Investigations are reported in the literature, by means of experimental, analytical and numerical methods, concerning the biomechanical properties of bone. However, the evolutionary phenomena of bone fracture healing does not have a large reference literature. This work investigates and describes the behaviour of inclined human femur fractures with external fixation up to complete healing. A numerical formulation based on the finite element method has been adopted. Geometric configuration is defined using data from a magnetic resonance process applied to a femur in vivo. A three dimensional model has been developed by adopting an orthotropic material law for cortical bone and an isotropic law for the fracture gap zone. Stress and strain reponses of the bone and fixation device are investigated with reference to the evolutionary behaviour of the healing tissue.     

A water-centred framework to assess the effects of salinity on the growth and yield of wheat and barley

We conducted a field experiment in two alpine meadows to investigate the short-term effects of nitrogen enrichment and plant litter biomass on plant species richness, the percent cover of functional groups, soil microbial biomass, and enzyme activity in two alpine meadow communities. The addition of nitrogen fertilizer to experimental plots over two growing seasons increased plant production, as indicated by increases in both the living plant biomass and litter biomass in the Kobresia humilis meadow community. In contrast, fertilization had no significant effect on the amounts of living biomass and litter biomass in the K. tibetica meadow. The litter treatment results indicate that litter removal significantly increased the living biomass and decreased the litter biomass in the K. humilis meadow; however, litter-removal and litter-intact treatments had no impact on the amounts of living biomass and litter biomass in the K. tibetica meadow. Litter production depended on the degree of grass cover and was also influenced by nitrogen enrichment. The increase in plant biomass reflects a strong positive effect of nitrogen enrichment and litter removal on grasses in the K. humilis meadow. Neither fertilization nor litter removal had any impact on the grass biomass in the K. tibetica meadow. Sedge biomass was not significantly affected by either nutrient enrichment or litter removal in either alpine meadow community. The plant species richness decreased in the K. humilis meadow following nitrogen addition. In the K. humilis meadow, microbial biomass C increased significantly in response to the nitrogen enrichment and litter removal treatments. Enzyme activities differed depending on the enzyme and the different alpine meadow communities; in general, enzyme activities were higher in the upper soil layers (0–10 cm and 10–20 cm) than in the lower soil layers (20–40 cm). The amounts of living plant biomass and plant litter biomass in response to the different treatments of the two alpine meadow communities affected the soil microbial biomass C, soil organic C, and soil fertility. These results suggest that the original soil conditions, plant community composition, and community productivity are very important in regulating plant community productivity and microbial biomass and activity.     

Osteogenic growth peptide enhances the rate of fracture healing in rabbits

The discovery of growth factors, such as osteogenic growth peptide (OGP), that stimulate bone formation led to experiments to discover whether they can accelerate fracture healing. To determine whether OGP enhances the rate of healing in rabbits, fractures were made in the tibiae of New Zealand White rabbits and immobilized with either a plastic plate (unstable mechanical conditions), or a dynamic compression plate (stable mechanical conditions). OGP was administered to experimental animals by intravenous injection from day 4 until the day before sacrifice; control animals were not injected. After treatment with OGP, callus development under unstable mechanical conditions was accelerated. At 7 days, the cartilage in the centre of the callus was covered by bone and endochondral ossification had started; these events occur at 10 days in control fractures. Subsequently, endochondral ossification is completed earlier which allows the invasion of the fracture gap by cells, so that cortical union is complete by 21 to 28 days. In control fractures, bone is only beginning to form in the gaps at 28 days. There was no increase in the size of the callus in any of the experimental fractures compared to the untreated controls. Treatment with OGP has no observable effect on the rate of healing of fractures under stable mechanical conditions. These observations suggest that under unstable mechanical conditions only, the rate of callus formation and subsequent cortical healing is enhanced by treatment with OGP, but that the size of the callus is determined by mechanical and other factors.     

A mathematical model to study the effects of drug resistance and vasculature on the response of solid tumors to chemotherapy

A mathematical model is developed that describes the reduction in volume of a vascular tumor in response to specific chemotherapeutic administration strategies. The model consists of a system of partial differential equations governing intratumoral drug concentration and cancer cell density. In the model the tumor is treated as a continuum of two types of cells which differ in their proliferation rates and their responses to the chemotherapeutic agent. The balance between cell proliferation and death within the tumor generates a velocity field which drives expansion or regression of the spheroid. Insight into the tumor's response to therapy is gained by applying a combination of analytical and numerical techniques to the model equations.     

Multiple influences of a heparin-binding growth factor on neuronal development

Heparin-binding growth factor-2 (HBGF-2; also known as basic fibroblast growth factor) is mitogenic for most anchorage-dependent cells. It is shown here that HBGF-2 stimulates cell-substratum adhesion and neurite extension in the sympathetic nerve cell line PC12. When HBGF-2 is adsorbed to artificial extracellular matrices consisting of heparin or chondroitin sulfate, it causes the formation of cellular aggregates or circles of cells, respectively. HBGF-2 is also a nerve cell survival molecule, for it potentiates the survival of primary cultures of embryonic chick ciliary ganglion cells but not of embryonic neural retina cells. Finally, a series of synthetic peptides from the HBGF-2 sequence is described that selectively alter the biological effects of HBGF-2. The amphiphilic nature of one of these peptides is discussed with respect to its ability to stimulate cell adhesion.     

Computational simulation of fracture healing: influence of interfragmentary movement on the callus growth

Bone fractures heal through a complex process involving several cellular events. This healing process can serve to study factors that control tissue growth and differentiation from mesenchymal stem cells. The mechanical environment at the fracture site is one of the factors influencing the healing process and controls size and differentiation patterns in the newly formed tissue. Mathematical models can be useful to unravel the complex relation between mechanical environment and tissue formation. In this study, we present a mathematical model that predicts tissue growth and differentiation patterns from local mechanical signals. Our aim was to investigate whether mechanical stimuli, through their influence on stem cell proliferation and chondrocyte hypertrophy, predict characteristic features of callus size and geometry. We found that the model predicted several geometric features of fracture calluses. For instance, callus size was predicted to increase with increasing movement. Also, increases in size were predicted to occur through increase in callus diameter but not callus length. These features agree with experimental observations. In addition, spatial and temporal tissue differentiation patterns were in qualitative agreement with well-known experimental results. We therefore conclude that local mechanical signals can probably explain the shape and size of fracture calluses.