Impact of Digestive Inflammatory Environment and Genipin Crosslinking on Immunomodulatory Capacity of Injectable Musculoskeletal Tissue Scaffold.

The paracrine and autocrine processes of the host response play an integral role in the success of scaffold-based tissue regeneration. Recently, the immunomodulatory scaffolds have received huge attention for modulating inflammation around the host tissue through releasing anti-inflammatory cytokine. However, controlling the inflammation and providing a sustained release of anti-inflammatory cytokine from the scaffold in the digestive inflammatory environment are predicated upon a comprehensive understanding of three fundamental questions. (1) How does the release rate of cytokine from the scaffold change in the digestive inflammatory environment? (2) Can we prevent the premature scaffold degradation and burst release of the loaded cytokine in the digestive inflammatory environment? (3) How does the scaffold degradation prevention technique affect the immunomodulatory capacity of the scaffold? This study investigated the impacts of the digestive inflammatory environment on scaffold degradation and how pre-mature degradation can be prevented using genipin crosslinking and how genipin crosslinking affects the interleukin-4 (IL-4) release from the scaffold and differentiation of naïve macrophages (M0). Our results demonstrated that the digestive inflammatory environment (DIE) attenuates protein retention within the scaffold. Over 14 days, the encapsulated protein released 46% more in DIE than in phosphate buffer saline (PBS), which was improved through genipin crosslinking. We have identified the 0.5 (w/v) genipin concentration as an optimal concentration for improved IL-4 released from the scaffold, cell viability, mechanical strength, and scaffold porosity, and immunomodulation studies. The IL-4 released from the injectable scaffold could differentiate naïve macrophages to an anti-inflammatory (M2) lineage; however, upon genipin crosslinking, the immunomodulatory capacity of the scaffold diminished significantly, and pro-inflammatory markers were expressed dominantly.

Time Course of Immune Response and Immunomodulation During Normal and Delayed Healing of Musculoskeletal Wounds.

Single trauma injuries or isolated fractures are often manageable and generally heal without complications. In contrast, high-energy trauma results in multi/poly-trauma injury patterns presenting imbalanced pro- and anti- inflammatory responses often leading to immune dysfunction. These injuries often exhibit delayed healing, leading to fibrosis of injury sites and delayed healing of fractures depending on the intensity of the compounding traumas. Immune dysfunction is accompanied by a temporal shift in the innate and adaptive immune cells distribution, triggered by the overwhelming release of an arsenal of inflammatory mediators such as complements, cytokines and damage associated molecular patterns (DAMPs) from necrotic cells. Recent studies have implicated this dysregulated inflammation in the poor prognosis of polytraumatic injuries, however, interventions focusing on immunomodulating inflammatory cellular composition and activation, if administered incorrectly, can result in immune suppression and unintended outcomes. Immunomodulation therapy is promising but should be conducted with consideration for the spatial and temporal distribution of the immune cells during impaired healing. This review describes the current state of knowledge in the spatiotemporal distribution patterns of immune cells at various stages during musculoskeletal wound healing, with a focus on recent advances in the field of Osteoimmunology, a study of the interface between the immune and skeletal systems, in long bone fractures. The goals of this review are to (1) discuss wound and fracture healing processes of normal and delayed healing in skeletal muscles and long bones; (2) provide a balanced perspective on temporal distributions of immune cells and skeletal cells during healing; and (3) highlight recent therapeutic interventions used to improve fracture healing. This review is intended to promote an understanding of the importance of inflammation during normal and delayed wound and fracture healing. Knowledge gained will be instrumental in developing novel immunomodulatory approaches for impaired healing.

Ultrasound is not associated with the presence of systemic autoimmunity or symptoms in individuals at risk for rheumatoid arthritis.

Objective: To identify whether musculoskeletal ultrasound (MSUS) abnormalities are associated with specific phases of rheumatoid arthritis (RA) development in individuals at risk of RA. Methods: This is a prospective cohort study of individuals at risk of developing RA, namely first-degree relatives of patients with RA (RA-FDRs) without evidence of established rheumatic disease at inclusion. The inflammatory activity on MSUS was assessed according to a validated score (SONAR). Active MSUS was defined as a total B-mode score greater than 8, including at least one joint with significant synovitis (grade 2 or 3) or significant synovial hyperaemia (Doppler score greater than 1). We used logistic regression to analyse associations between MSUS findings and recognised preclinical phases of RA development, adjusting for other demographic and biological characteristics. Results: A total of 273 RA-FDRs were analysed, of whom 23 (8%) were anticitrullinated protein autoantibodies-positive, 58 (21%) had unclassified arthritis and 96 (35%) had an active MSUS, which was only associated with unclassified arthritis (OR: 1.8, 95% CI 1.0 to 3.3). Conclusion: In individuals at risk of RA, active MSUS was associated with the presence of unclassified arthritis, but not with any of the earlier described phases of RA development. These findings do not support an indiscriminate use of ultrasound in a screening strategy for preclinical RA.

[THE SYSTEMIC IMMUNITY CELLULAR LINK REACTION IN PATIENTS WITH TRAUMATIC ILLNESS].

The effect of trauma on parameters of cellular immunity changes is studied. The study includes 52 patients with various forms of traumatic illness, aged 18-69 years (37.91-4.28). The control group consisted of 16 patients who underwent routine surgery not related to the pathology of musculoskeletal system. All patients of the main group were divided into 3 groups according to severity of the condition. Analysis of parameters of cellular link of immune system was performed by defining subpopulations of T-lymphocytes in indirect immunofluorescence method using a panel of monoclonal antibodies for CD3, CD4, CD8, CD22 lymphocytes' receptors and calculation of integrated indicators. The highest expression (immune disorders of II-III grades) of changes of cellular immunity observed in patients with severe traumatic: illness (expand clinical picture). Surgical intervention, even without traumatic injury significantly impact cellular immunity, but in patients with traumatic illness immunity violation were significantly higher than in comparison groups patients except immunoregulatory index.

Does complement play a role in bone development and regeneration?

The skeletal and the immune system are not two independent systems, rather, there are multifaceted and complex interactions between the different cell types of both systems and there are several shared cytokines. As a part of the innate immunity, the complement system was found to be an important link between bone and immunity. Complement proteins appear to be involved in bone development and homeostasis, and specifically influence osteoblast and osteoclast activity. This review describes the complex mutual regulation of the two systems, and indicates some of the negative side effects as a result of inappropriate or excessive complement activation.

Immune depression in musculoskeletal trauma.

The immune responses after musculoskeletal trauma are physiological reactions of the organism to restore homeostasis. An imbalance between the early systemic inflammatory response syndrome and the later compensatory anti-inflammatory response syndrome may be responsible for organ dysfunction and increased susceptibility to infections. Cytokines are known to be integral components of the immune response, and the balance or imbalance of the different cytokines partly controls the clinical course in the patients. The major pro-inflammatory cytokines include tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), IL-6, and IL-8. These cytokines are predominantly produced by monocytes and macrophages, they mediate overlapping effects, and their actions can be additive. TNF-alpha and IL-1beta are early regulators of the immune response, and both induce the release of secondary pro-inflammatory cytokines. IL-10 is an anti-inflammatory cytokine which reduces the synthesis of pro-inflammatory mediators. The extent of traumatic damage correlates with the immunological changes and determines a graded depression of leucocytes to express cytokines on edotoxin exposure. Correspondingly, it has become clinically evident that in unstable traumatised patients, the recommendation today is damage control orthopaedics, i.e. initial stabilisation of long bone fractures by external fixation followed by definitive stabilisation at about 1 week.

Osteomyelitis and arthritis.

Infections of bone and the joints can represent major diagnostic and therapeutic challenges to all clinicians. Together with osteomyelitis and septic arthritis, soft-tissue infections like cellulites/fasciitis and abscess formation can occur, which have to be treated appropriately. Bone scintigraphy is a sensitive method that can be used to search for bone and joint infections. Labeled leukocytes often are used as the gold standard to identify infectious foci in the musculoskeletal system, but major drawbacks of this method are the imaging of chronic infections and imaging of the axial skeleton. Like (111)In-labeled leukocyte imaging, (99m)Tc-labeled antigranulocyte antibody scintigraphy has a role in the imaging of osteomyelitis of the peripheral skeleton. Magnetic resonance imaging is widely used to evaluate musculoskeletal infections and is excellent in identifying abscess formation, but the extent and spread of infection is sometimes difficult to delineate because hyperemia and infection are not congruent.

Proinflammatory markers in prediction of posttraumatic psychological symptoms: a prospective cohort study.

INTRODUCTION: Posttraumatic psychopathology (PTP) describes the spectrum of conditions that can complicate the recovery from commonly occurring musculoskeletal trauma. There is a clear association with the activation of the hypothalamic-pituitary-adrenal axis (HPAA), and we wished to examine the predictive value of proinflammatory markers of the HPAA and of the GABA, which acts as an inhibitory regulator. METHODS: Levels of proinflammatory markers and GABA were measured in 84 patients who had suffered musculoskeletal injuries requiring hospitalisation. PTP was assessed by the use of the General Health Questionnaire (GHQ) at presentation and again at two- and six-month reviews. RESULTS: Significant psychological disturbance was noted in 39% of patients at two months and falling back to 18% by six months. There was no correlation between any of the markers tested at presentation and PTP at follow-up. DISCUSSION: The HPAA response to trauma and the development of PTP are extremely complex. It is unlikely that a simple blood assay will provide significant predictive information, while incident specific information and patient perception are of more practical use.

The immune response: the afferent arm.

The key to understanding afferent immunity is the mechanism of activation of T lymphocytes by specialized antigen presenting cells, which bind antigenic peptide to Class II major histocompatibility molecules, and stimulate T cells via Signal 1 (antigen) and Signal 2 (costimulation). The best studied costimulatory pathway is the interaction of B7-1 or B7-2 ligand molecules on antigen presenting cells with CD28 or CTLA-4 receptors on T cells. T cell signaling occurs through the T cell receptor-CD3 complex and is augmented by cosignaling via CD4, CD8, and CD45. The activation of T cells to alloantigen occurs by either a direct pathway of recognition of allogenic major histocompatibility molecules (with or without an associated endogenous peptide), or by an indirect pathway of recognition of processed donor alloantigens via recipient antigen presenting cells. Afferent immunity on the musculoskeletal system is of special interest because of the absence of viable donor antigen presenting cells in processed grafts that makes them susceptible to the indirect pathway of alloantigen recognition.

An overview of neuroimmunomodulation and a possible correlation with musculoskeletal system function.

There is an increasing body of evidence that the nervous system is capable of modulating the immune response. Receptors for neuromodulators and neurohormones have been found on human T lymphocytes. Activation of these receptors can be stimulatory or inhibitory depending on the neuroactive substance. The immune system may be able to communicate with the nervous system using neuromodulators and neurohormones secreted by lymphocytes. Sympathetic innervation of lymphoid tissues is not restricted to blood vessels and smooth muscle, but directly supplies lymphocytes and blood precursor cells. It is theorized that spinal fixations may adversely affect the immune response through somatosympathetic reflexes. Spinal manipulation can correct the spinal fixations and may eliminate the adverse affects of somatosympathetic reflexes.