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Tendon healing is characterized by the formation of fibrovascular scar tissue, as tendon has very little intrinsic regenerative capacity. This creates a substantial clinical challenge in the setting of large, chronic tears seen clinically. Interest in regenerative healing seen in amphibians and certain strains of mice has arisen in response to the biological behavior of tendon tissue. Bone is also a model of tissue regeneration as healing bone will achieve the mechanical and histologic characteristics of the original tissue. The ultimate goal of the study of genes and mechanisms that contribute to true tissue regeneration is to ultimately attempt to manipulate the expression of those genes and activate these mechanisms in the setting of tendon injury and repair. Clearly, further research is needed to bring this to the forefront, however, study of scarless healing has potential to have meaningful application to tendon healing.

Tendinopathy and tendon rupture are common and disabling musculoskeletal conditions. Despite the prevalence of these injuries, a limited number of investigators are conducting fundamental, basic science studies focused on understanding processes governing tendinopathies and tendon healing. Development of effective therapeutics is hindered by the lack of fundamental guiding data on the biology of tendon development, signal transduction, mechanotransduction, and basic mechanisms underlying tendon pathogenesis and healing. To propel much needed progress, the New Frontiers in Tendon Research Conference, co-sponsored by NIAMS/NIH, the Orthopaedic Research Society, and the Icahn School of Medicine at Mount Sinai, was held to promote exchange of ideas between tendon researchers and basic science experts from outside the tendon field. Discussed research areas that are underdeveloped and represent major hurdles to the progress of the field will be presented in this review. To address some of these outstanding questions, conference discussions and breakout sessions focused on six topic areas (Cell Biology and Mechanics, Functional Extracellular Matrix, Development, Mechano-biology, Scarless Healing, and Mechanisms of Injury and Repair), which are reviewed in this special issue and briefly presented in this review. Review articles in this special issue summarize the progress in the field and identify essential new research directions.

Although there have been several advances identifying novel mediators of tendon induction, differentiation, and patterning, much of the basic landscape of tendon biology from developmental stages onward remain almost completely undefined. During the New Frontiers in Tendon Research meeting, a group of developmental biologists with expertise across musculoskeletal disciplines identified key challenges for the tendon development field. The tools generated and the molecular regulators identified in developmental research have enhanced mechanistic studies in tendon injury and repair, both by defining benchmarks for success, as well as informing regenerative strategies. To address the needs of the orthopedic research community, this review will therefore focus on three key areas in tendon development that may have critical implications for the fields of tendon repair/regeneration and tendon tissue engineering, including functional markers of tendon cell identity, signaling regulators of tendon induction and differentiation, and in vitro culture models for tendon cell differentiation. Our goal is to provide a useful list of the currently known molecular players and their function in tendon differentiation within the context of development.

Skeletal muscle injury is common in everyday physical activity and athletics, as well as in orthopedic trauma and disease. The overall functional disability resulting from muscle injury is directly related to the intrinsic healing properties of muscle and extrinsic treatment options designed to maximize repair and/or regeneration of muscle tissue all while minimizing pathologic healing pathways. It is important to understand the injury and repair pathways in order to improve the speed and quality of recovery. Recent military conflicts in Iraq and Afghanistan have highlighted the importance of successfully addressing muscular injury and showed the need for novel treatment options that will maximize functional regeneration of the damaged tissue. These severe, wartime injuries, when juxtaposed to peacetime, sports-related injuries, provide us with interesting case examples of the two extreme forms of muscular damage. Comparing and contrasting the differences in these healing pathways will likely provide helpful cues that will help physicians recapitulate the near complete repair and regeneration in less traumatic injuries in addition to more severe cases.

Anterior cruciate ligament (ACL) injuries are currently treated by removing the injured ligament and replacing it with a tendon graft. Recent studies have examined alternative treatment methods, including repair and regeneration of the injured ligament. In order to make such an approach feasible, a basic understanding of ACL biology and its response to injury is needed. Identification of obstacles to native ACL healing can then be identified and potentially resolved using tissue engineering strategies-first, with in vitro screening assays, and then with in vivo models of efficacy and safety. This Perspectives paper outlines this path of discovery for optimizing ACL healing using a bio-enhanced repair technique. This journey required constructing indices of the functional tissue response, pioneering physiologically based methods of biomechanical testing, developing, and validating clinically relevant animal models, and creating and optimizing translationally feasible scaffolds, surgical techniques, and biologic additives. Using this systematic translational approach, "bio-enhanced" ACL repair has been advanced to the point where it may become an option for future treatment of acute ACL injuries and the prevention of subsequent post-traumatic osteoarthritis associated with this injury.

While neurovascular diseases such as ischemic and hemorrhagic stroke are the leading causes of disability in the world, the repertoire of therapeutic interventions has remained remarkably limited. There is a dire need to develop new diagnostic, prognostic, and therapeutic options. The study of proteomics is particularly enticing for cerebrovascular diseases such as stroke, which most likely involve multiple gene interactions resulting in a wide range of clinical phenotypes. Currently, rapidly progressing neuroproteomic techniques have been employed in clinical and translational research to help identify biologically relevant pathways, to understand cerebrovascular pathophysiology, and to develop novel therapeutics and diagnostics. Future integration of proteomic with genomic, transcriptomic, and metabolomic studies will add new perspectives to better understand the complexities of neurovascular injury. Here, we review cerebrovascular proteomics research in both preclinical (animal, cell culture) and clinical (blood, urine, cerebrospinal fluid, microdialyates, tissue) studies. We will also discuss the rewards, challenges, and future directions for the application of proteomics technology to the study of various disease phenotypes. To capture the dynamic range of cerebrovascular injury and repair with a translational targeted and discovery approach, we emphasize the importance of complementing innovative proteomic technology with existing molecular biology models in preclinical studies, and the need to advance pharmacoproteomics to directly probe clinical physiology and gauge therapeutic efficacy at the bedside.

The human endometrium is exposed to repeated inflammation every month, culminating in tissue breakdown and menstruation. Subsequently, the endometrium has a remarkable capacity for efficient repair and remodeling to enable implantation if fertilization takes place. Endometrial function is known to be governed by the ovarian hormones estradiol and progesterone. This review paper focuses on hormonal control of the cyclical tissue injury and repair that takes place in the local endometrial environment at the time of menstruation. Progesterone levels decline premenstrually as the corpus luteum regresses in the absence of pregnancy, and estradiol levels increase during the postmenstrual phase. The functional impact of these significant changes is discussed, including their immediate and downstream effects. Finally, we examine the contribution of aberrant endometrial function to the presentation of heavy menstrual bleeding and identify potential therapeutic targets for the treatment of this common gynecological problem.

Tissue injury in the oral mucosa activates a cascade of transcriptional events important during the healing process that are not yet clearly defined. To characterize these events and identify potential gene targets for future studies, we used cDNA expression arrays in a clinical model of tissue injury. Mucosal biopsies were taken before third molar extraction, 2-4 hours postoperatively, or at 48 hours. Hybridization patterns were analyzed and validated using real-time polymerase chain reaction. Prior to extraction, the biopsied mucosal tissues were characterized by a panoply of genes that were constitutively expressed. After injury, analysis revealed differential expression of genes involved in transcription, inflammation, and remodeling. At 2-4 hours after injury, genes such as Fos, Jun, and early growth response protein were up-regulated, while genes responsible for intercellular adhesion were down-regulated. At 48 hours after injury, the gene profile had shifted toward tissue remodeling. Here we identify genes constitutively expressed in normal oral mucosa and transcriptional events following mucosal tissue injury, which may be useful in identifying new therapeutic targets.

The metabolic response of the rhesus macaque brain during acute simian immunodeficiency virus (SIV) infection was investigated with in vivo 1H MR spectroscopy. Fifteen rhesus macaques were studied before inoculation, and once or twice after infection. In all, 13/15 macaques had elevations of Cho/NAA at 11–13 days postinoculation (dpi); all 10 macaques measured after 13 dpi had subsequent reduction of this ratio (ANOVA, P < 10-6). There were significant increases in Cho/Cr (20%, P = 0.04) and MI/Cr (14%, P = 0.003) at 11 dpi. At 13 dpi a 7.7% decrease (P = 0.02) in NAA/Cr was observed, while Cho/Cr was no longer significantly different from baseline. At 27 dpi Cho/Cr was decreased to 18% (P = 0.004) below preinoculation values, while NAA/Cr and MI/Cr were at baseline values. Absolute concentrations of Cho, MI, and NAA showed a similar time course, with no observed changes in Cr. There was a strong correlation between Cho/Cr change and plasma viral load (rs = 0.79, P < 0.01). Acute SIV produces extensive metabolic abnormalities in the brain, which may reflect inflammation and neuronal injury, which are reversed with immunological control of the virus. Similar events are likely to occur in acutely HIV-infected people, and may explain the neurobehavioral symptoms associated with acute HIV infection. Magn Reson Med 51:1108–1114, 2004. © 2004 Wiley-Liss, Inc.

Water molecules associated with collagen have short transverse (T2) relaxation times. Projection-reconstruction techniques are able to achieve an echo time (TE) much shorter than conventional techniques, allowing imaging of tissues with T2 < 5 ms. Using these techniques, a conventional 1.5-T MRI human imaging system can directly image collagen-associated water from knee menisci and tendons in normal volunteers and patients. Long-T2 suppression improves the contrast between these structures and the surrounding tissue with long-T2 relaxation times. Spectroscopic imaging provides improved lipid/water registration and information about chemical composition and relaxation times. Direct imaging of tendons and menisci may provide more information about these structures and provide a new way to assess both injury and repair.

The type of sugar in the heating and recovery media affected the rate of inactivation and repair capability of a Chablis strain of Saccharomyces cerevisiae. The rate of heat inactivation decreased with decreasing aw in glucose and fructose but not in sucrose solutions. At any aw the order of susceptibility to inactivation of yeast cells was consistently: fructose, glucose, and sucrose. In fructose, a major proportion of the survivors exhibited sublethal injury. When suspended in solutions containing the various sugars after heating and incubated for up to 18 hr prior to plating, the type of sugar in the solution influenced the ability of cells to repair injury.