Wound healing, as a normal biological process in the human body, is achieved through four precisely and highly programmed phases: hemostasis, inflammation, proliferation, and remodeling For a wound to heal successfully, all four phases must occur in the proper sequence and time frame Many factors can interfere with one or more phases of this process, thus causing improper or impaired wound healing This article reviews the recent literature on the most significant factors that affect cutaneous wound healing and the potential cellular and/or molecular mechanisms involved The factors discussed include oxygenation, infection, age and sex hormones, stress, diabetes, obesity, medications, alcoholism, smoking, and nutrition A better understanding of the influence of these factors on repair may lead to therapeutics that improve wound healing and resolve impaired wounds

Factors Affecting Wound Healing

RGD modified polymers: biomaterials for stimulated cell adhesion and beyond

Nature’s hierarchical materials

On the mechanisms of biocompatibility.

PLoS BIOLOGY Senescence-Associated Secretory Phenotypes Reveal Cell-Nonautonomous Functions of Oncogenic RAS and the p53 Tumor Suppressor Jean-Philippe Coppe 1 , Christopher K. Patil 1[ , Francis Rodier 1,2[ , Yu Sun 3 , Denise P. Mun oz 1,2 , Joshua Goldstein 1¤ , Peter S. Nelson 3 , Pierre-Yves Desprez 1,4 , Judith Campisi 1,2* 1 Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, United States of America, 2 Buck Institute for Age Research, Novato, California, United States of America, 3 Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America, 4 California Pacific Medical Center Research Institute, San Francisco, California, United States of America Cellular senescence suppresses cancer by arresting cell proliferation, essentially permanently, in response to oncogenic stimuli, including genotoxic stress. We modified the use of antibody arrays to provide a quantitative assessment of factors secreted by senescent cells. We show that human cells induced to senesce by genotoxic stress secrete myriad factors associated with inflammation and malignancy. This senescence-associated secretory phenotype (SASP) developed slowly over several days and only after DNA damage of sufficient magnitude to induce senescence. Remarkably similar SASPs developed in normal fibroblasts, normal epithelial cells, and epithelial tumor cells after genotoxic stress in culture, and in epithelial tumor cells in vivo after treatment of prostate cancer patients with DNA- damaging chemotherapy. In cultured premalignant epithelial cells, SASPs induced an epithelial–mesenchyme transition and invasiveness, hallmarks of malignancy, by a paracrine mechanism that depended largely on the SASP factors interleukin (IL)-6 and IL-8. Strikingly, two manipulations markedly amplified, and accelerated development of, the SASPs: oncogenic RAS expression, which causes genotoxic stress and senescence in normal cells, and functional loss of the p53 tumor suppressor protein. Both loss of p53 and gain of oncogenic RAS also exacerbated the promalignant paracrine activities of the SASPs. Our findings define a central feature of genotoxic stress-induced senescence. Moreover, they suggest a cell-nonautonomous mechanism by which p53 can restrain, and oncogenic RAS can promote, the development of age-related cancer by altering the tissue microenvironment. Citation: Coppe JP, Patil CK, Rodier F, Sun Y, Mun oz DP, et al. (2008) Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol 6(12): e301. doi:10.1371/journal.pbio.0060301 Introduction Cancer is a multistep disease in which cells acquire increasingly malignant phenotypes. These phenotypes are acquired in part by somatic mutations, which derange normal controls over cell proliferation (growth), survival, invasion, and other processes important for malignant tumorigenesis [1]. In addition, there is increasing evidence that the tissue microenvironment is an important determinant of whether and how malignancies develop [2,3]. Normal tissue environ- ments tend to suppress malignant phenotypes, whereas abnormal tissue environments such at those caused by inﬂammation can promote cancer progression. Cancer development is restrained by a variety of tumor suppressor genes. Some of these genes permanently arrest the growth of cells at risk for neoplastic transformation, a process termed cellular senescence [4–6]. Two tumor suppressor pathways, controlled by the p53 and p16INK4a/pRB proteins, regulate senescence responses. Both pathways integrate multiple aspects of cellular physiology and direct cell fate towards survival, death, proliferation, or growth arrest, depending on the context [7,8]. Several lines of evidence indicate that cellular senescence is a potent tumor-suppressive mechanism [4,9,10]. Many poten- tially oncogenic stimuli (e.g., dysfunctional telomeres, DNA PLoS Biology | www.plosbiology.org damage, and certain oncogenes) induce senescence [6,11]. Moreover, mutations that dampen the p53 or p16INK4a/pRB pathways confer resistance to senescence and greatly increase cancer risk [12,13]. Most cancers harbor mutations in one or both of these pathways [14,15]. Lastly, in mice and humans, a senescence response to strong mitogenic signals, such as those delivered by certain oncogenes, prevents premalignant lesions from progressing to malignant cancers [16–19]. Academic Editor: Julian Downward, Cancer Research UK, United Kingdom Received June 27, 2008; Accepted October 22, 2008; Published December 2, 2008 Copyright: O 2008 Coppe et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Abbreviations: CM, conditioned medium; DDR, DNA damage response; ELISA, enzyme-linked immunosorbent assay; EMT, epithelial–mesenchymal transition; GSE, genetic suppressor element; IL, interleukin; MIT, mitoxantrone; PRE, presenescent; PrEC, normal human prostate epithelial cell; REP, replicative exhaustion; SASP, senescence-associated secretory phenotype; SEN, senescent; shRNA, short hairpin RNA; XRA, X-irradiation * To whom correspondence should be addressed. E-mail: jcampisi@lbl.gov [ These authors contributed equally to this work. ¤ Current address: Genomics Institute of the Novartis Research Foundation, San Diego, California, United States of America December 2008 | Volume 6 | Issue 12 | e301

Senescence-Associated Secretory Phenotypes Reveal Cell-Nonautonomous Functions of Oncogenic RAS and the p53 Tumor Suppressor

Study design We conducted intradiscal pressure measurements with one volunteer performing various activities normally found in daily life, sports, and spinal therapy. Objectives The goal of this study was to measure intradiscal pressure to complement earlier data from Nachemson with dynamic and long-term measurements over a broad range of activities. Summary of background data Loading of the spine still is not well understood. The most important in vivo data are from pioneering intradiscal pressure measurements recorded by Nachemson during the 1960s. Since that time, there have been few data to corroborate or dispute those findings. Methods Under sterile surgical conditions, a pressure transducer with a diameter of 1.5 mm was implanted in the nucleus pulposus of a nondegenerated L4-L5 disc of a male volunteer 45-years-old and weighing 70 kg. Pressure was recorded with a telemetry system during a period of approximately 24 hours for various lying positions; sitting positions in a chair, in an armchair, and on a pezziball (ergonomic sitting ball); during sneezing, laughing, walking, jogging, stair climbing, load lifting during hydration over 7 hours of sleeping, and others. Results The following values and more were measured: lying prone, 0.1 MPa; lying laterally, 0.12 MPa; relaxed standing, 0.5 MPa; standing flexed forward, 1.1 MPa; sitting unsupported, 0.46 MPa; sitting with maximum flexion, 0.83 MPa; nonchalant sitting, 0.3 MPa; and lifting a 20-kg weight with round flexed back, 2.3 MPa; with flexed knees, 1.7 MPa; and close to the body, 1.1 MPa. During the night, pressure increased from 0.1 to 0.24 MPa. Conclusions Good correlation was found with Nachemson's data during many exercises, with the exception of the comparison of standing and sitting or of the various lying positions. Notwithstanding the limitations related to the single-subject design of this study, these differences may be explained by the different transducers used. It can be cautiously concluded that the intradiscal pressure during sitting may in fact be less than that in erect standing, that muscle activity increases pressure, that constantly changing position is important to promote flow of fluid (nutrition) to the disc, and that many of the physiotherapy methods studied are valid, but a number of them should be re-evaluated.

http://www.fonar.com/pdf/spine_vol_24.No.8.pdf

New in vivo measurements of pressures in the intervertebral disc in daily life.

Optimal fracture treatment requires knowledge of the complex physiological process of bone healing. The course of bone healing is mainly influenced by fracture fixation stability (biomechanics) and the blood supply to the healing site (revascularization after trauma). The repair process proceeds via a characteristic sequence of events, described as the inflammatory, repair and remodeling phases. An inflammatory reaction involving immune cells and molecular factors is activated immediately in response to tissue damage and is thought to initiate the repair cascade. Immune cells also have a major role in the repair phase, exhibiting important crosstalk with bone cells. After bony bridging of the fragments, a slow remodeling process eventually leads to the reconstitution of the original bone structure. Systemic inflammation, as observed in patients with rheumatoid arthritis, diabetes mellitus, multiple trauma or sepsis, can increase fracture healing time and the rate of complications, including non-unions. In addition, evidence suggests that insufficient biomechanical conditions within the fracture zone can influence early local inflammation and impair bone healing. In this Review, we discuss the main factors that influence fracture healing, with particular emphasis on the role of inflammation.

Fracture healing under healthy and inflammatory conditions

New implants and new surgical approaches should be tested in vitro for primary stability in standardized laboratory tests in order to decide the most appropriate approach before being accepted for clinical use. Due to the complex and still unknown loading of the spine in vivo a variety of different test loading conditions have been used, making comparison of the results from different groups almost impossible. This recommendation was developed in a series of workshops with research scientists, orthopedic and trauma surgeons, and research and development executives from spinal implant companies. The purpose was to agree on in vitro testing conditions that would allow results from various research groups to be compared. This paper describes the recommended loading methods, specimen conditions, and analysis parameters resulting from these workshops.

Testing criteria for spinal implants: recommendations for the standardization of in vitro stability testing of spinal implants

http://www.biomechanics.ru/lib/files/32_0255.pdf

Magnitudes of local stress and strain along bony surfaces predict the course and type of fracture healing

Study design This study investigated the influence of five different muscle groups on the monosegmental motion (L4-L5) during pure flexion/extension, lateral bending, and axial rotation moments. Objectives The results showed and compared the effect of different muscle groups acting in different directions on the stability of a single motion segment to find loading conditions for in vitro experiments that simulate more physiologically reasonable loads. Summary of background data In spine biomechanics research, most in vitro experiments have been carried out without applying muscle forces, even though these forces stabilize the spinal column in vivo. Methods Seven human lumbosacral spines were tested in a spine tester that allows simulation of up to five symmetrical muscle forces. Changing pure flexion/extension, lateral bending, and axial rotation moments up to +/- 3.75 Nm were applied without muscle forces, with different muscle groups and combinations. The three-dimensional monosegmental motion was determined using an instrumented spatial linkage system. Results Simulated muscle forces were found to strongly influence load-deformation characteristics. Muscle action generally decreased the range of motion and the neutral zone of the motion segments. This was most evident for flexion and extension. After five pairs of symmetrical, constant muscle forces were applied (80 N per pair), the range of motion decreased about 93% in flexion and 85% in extension. The total neutral zone for flexion and extension was decreased by 83% muscle action. The multifidus muscle group had the strongest influence. Conclusion This experiment showed the importance of including at least some of the most important muscle groups in in vitro experiments on lumbar spine specimens.

Lutz Claes

Papers

New in vivo measurements of pressures in the intervertebral disc in daily life.

Fracture healing under healthy and inflammatory conditions

Testing criteria for spinal implants: recommendations for the standardization of in vitro stability testing of spinal implants

Magnitudes of local stress and strain along bony surfaces predict the course and type of fracture healing

Stability increase of the lumbar spine with different muscle groups. A biomechanical in vitro study.