Citations

Objectives: To develop and validate an unbiased, accurate, convenient, and inexpensive means of determining when an osseous defect has healed and recovered sufficient strength to allow weight bearing. Methods: A novel image processing software algorithm was created to analyze the radiographic images and produce a metric designed to reflect the bone strength. We used a rat femoral segmental defect model that provides a range of healing responses from complete union to nonunion. Femora were examined by x-ray, micro–computed tomography and mechanical testing. Accurate simulated radiographic images at different incident x-ray beam angles were produced from the micro–computed tomography data files. Results: The software-generated metric (SC) showed high levels of correlation with both the mechanical strength (τMech) and the polar moment of inertia (pMOI), with the mechanical testing data having the highest association. The optimization analysis yielded optimal oblique angles θB of 125 degrees for τMech and 50 degrees for pMOI. The Pearson R2 values for the optimized model were 0.71 and 0.64 for τMech and pMOI, respectively. Further validation using true radiographs also demonstrated that the metric was accurate and that the simulations were realistic. Conclusions: The preliminary findings suggest a very promising methodology to assess bone fracture healing using conventional radiography. With radiographs acquired at appropriate incident angles, it proved possible to accurately calculate the degree of healing and the mechanical strength of the bone. Further research is necessary to refine this approach and determine whether it translates to the human clinical setting.

Background: The role of the paratenon in tendon healing is unknown. The present study compares healing in the presence or absence of the paratenon in an Achilles tendon defect model in rats. Hypothesis: Resection of the paratenon impairs tendon healing. Study Design: Controlled laboratory study. Methods: Sixty skeletally mature Sprague Dawley rats were randomly assigned to either a resected paratenon (RP) group or an intact paratenon (IP) group. In all animals, a 4-mm portion of the Achilles tendon was resected in the midsubstance. In the RP group, the paratenon was resected completely. In the IP group, the paratenon was opened longitudinally and closed again after the tendon defect had been created. One, 2, and 4 weeks after surgery, 7 animals per group were tested biomechanically and 3 animals per group examined histologically. Results: The recovery of mechanical strength was much more rapid in IP tendons. Tear resistance was significantly increased for IP tendons (41.3 ± 8.8 N and 47.3 ± 14.1 N, respectively) compared with RP tendons (19.3 ± 9.1 N and 33.2 ± 6.4 N, respectively) after 1 and 2 weeks. The cross-sectional area was larger in the IP group after 1 and 2 weeks (8.2 ± 2.3 mm 2 and 11.3 ± 3.1 mm 2 vs 5.0 ± 2.4 mm 2 and 5.9 ± 2.0 mm 2 , respectively) compared with the RP group. Tendon stiffness was greater in the IP group after 1 week (10.4 ± 1.9 N/mm vs 4.5 ± 1.6 N/mm, respectively) compared with the RP group. In comparison, normal contralateral tendons had a maximal tear resistance of 56.6 ± 7.2 N, a cross-sectional area of 3.6 ± 0.7 mm 2 , and stiffness of 17.3 ± 3.8 N/mm. Hematoxylin and eosin staining revealed slightly delayed healing of RP tendons. Early collagen formation was seen in the IP group already after 1 week, whereas in the RP group, this only occurred after 2 weeks. After 4 weeks, the IP tendons showed more collagen crimp formation than the RP tendons. Conclusion: An intact paratenon promotes healing of the Achilles tendon. Clinical Relevance: Although incision or resection of the paratenon has been advocated when repairing injured or degenerative tendons, our data suggest that the integrity of the paratenon should be preserved.

M2muscarinic receptors limit acetylcholine release from the pulmonary parasympathetic nerves. M2receptors are dysfunctional in antigen-challenged guinea pigs, causing increased vagally mediated bronchoconstriction. Dysfunction of these M2receptors is due to eosinophil major basic protein, which is an antagonist for M2receptors. Histamine-induced bronchoconstriction is composed of a vagal reflex in addition to its direct effect on airway smooth muscle. Because hyperreactivity to histamine is seen in antigen-challenged animals, we hypothesized that hyperreactivity to histamine may be due to increased vagally mediated bronchoconstriction caused by dysfunction of M2receptors. In anesthetized, antigen-challenged guinea pigs, histamine-induced bronchoconstriction was greater than that in control guinea pigs. After vagotomy or atropine treatment, the response to histamine in antigen-challenged animals was the same as that in control animals. In antigen-challenged animals, blockade of eosinophil influx into the airways or neutralization of eosinophil major basic protein prevented the development of hyperreactivity to histamine. Thus hyperreactivity to histamine in antigen-challenged guinea pigs is vagally mediated and dependent on eosinophil major basic protein.

Neuronal muscarinic (M2) receptors inhibit release of acetylcholine from the vagus nerves. Hyperreactivity in antigen-challenged guinea pigs is due to blockade of these M2autoreceptors by eosinophil major basic protein (MBP) increasing the release of acetylcholine. In vivo, substance P-induced hyperactivity is vagally mediated. Because substance P induces eosinophil degranulation, we tested whether substance P-induced hyperreactivity is mediated by release of MBP and neuronal M2receptor dysfunction. Pathogen-free guinea pigs were anesthetized and ventilated. Thirty minutes after intravenous administration of [Sar9,Met(O2)11]- substance P, guinea pigs were hyperreactive to vagal stimulation and M2receptors were dysfunctional. The depletion of inflammatory cells with cyclophosphamide or the administration of an MBP antibody or a neurokinin-1 (NK1) receptor antagonist (SR-140333) all prevented substance P-induced M2dysfunction and hyperreactivity. Intravenous heparin acutely reversed M2receptor dysfunction and hyperreactivity. Thus substance P releases MBP from eosinophils resident in the lungs by stimulating NK1receptors. Substance P-induced hyperreactivity is mediated by blockade of inhibitory neuronal M2receptors by MBP, resulting in increased release of acetylcholine.

Most forms of arthritis are incurable, difficult to treat, and a major cause of disability in Western countries. Better local treatment of arthritis is impaired by the pharmacokinetics of the joint that make it very difficult to deliver drugs to joints at sustained, therapeutic concentrations. This is especially true of biologic drugs, such as proteins and RNA, many of which show great promise in preclinical studies. Gene transfer provides a strategy for overcoming this limitation. The basic concept is to deliver cDNAs encoding therapeutic products by direct intra-articular injection, leading to sustained, endogenous synthesis of the gene products within the joint. Proof of concept has been achieved for both in vivo and ex vivo gene delivery using a variety of vectors, genes, and cells in several different animal models. There have been a small number of clinical trials for rheumatoid arthritis (RA) and osteoarthritis (OA) using retrovirus vectors for ex vivo gene delivery and adeno-associated virus (AAV) for in vivo delivery. AAV is of particular interest because, unlike other viral vectors, it is able to penetrate deep within articular cartilage and transduce chondrocytes in situ. This property is of particular importance in OA, where changes in chondrocyte metabolism are thought to be fundamental to the pathophysiology of the disease. Authorities in Korea have recently approved the world's first arthritis gene therapy. This targets OA by the injection of allogeneic chondrocytes that have been transduced with a retrovirus carrying transforming growth factor-β 1 cDNA. Phase III studies are scheduled to start in the United States soon. Meanwhile, two additional Phase I trials are listed on Clinicaltrials.gov , both using AAV. One targets RA by transferring interferon-β, and the other targets OA by transferring interleukin-1 receptor antagonist. The field is thus gaining momentum and promises to improve the treatment of these common and debilitating diseases.

Osteoarthritis is a painful, chronic disease with widespread burden on patients, communities, health and social care systems. Conservative therapies, such as nonpharmacological interventions, systemic drug treatment and intra-articular therapies are used before resorting to surgery; nonetheless, disease control often remains inadequate. Recent advances in osteoarthritis management have aimed to provide greater variety of treatment options. Here, we summarize a targeted literature review evaluating efficacy and safety of intra-articular therapies for osteoarthritis. Injections of intra-articular therapies directly into the joint avoid conventional barriers to joint entry, increase bioavailability and lower systemic toxicity. Intra-articular corticosteroids and hyaluronic acid are established United States Food and Drug Administration (US FDA)/European Medicines Agency (EMA)-approved treatments; however, concerns exist regarding effect duration, safety, effectiveness across populations and heterogeneity. Newer therapies, such as autologous blood products and mesenchymal stem cells, are in development. Benefits of autologous blood products (e.g. platelet-rich plasma, autologous conditioned serum) include an expected improved safety profile and direct targeting of osteoarthritis-related pathophysiology. Autologous conditioned serum is cell-free and manufactured by a standardized process, whereas platelet-rich plasma composition and characteristics can vary. Currently, only limited efficacy comparisons between these biological treatments can be drawn; long-term clinical and safety studies are needed to increase the efficacy evidence base and earn consideration in treatment frameworks.