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      Development of dual delivery antituberculotic system containing rifapentine microspheres and adipose stem cells seeded in hydroxyapatite/tricalcium phosphate

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          Low drug concentration in the tuberculosis (TB) lesion and bone defects or nonunion after debridement are two major problems that occur in the course of treating osteo-articular TB. Thus, the combination of drug-delivery system and bone tissue repair appears to be the most promising option for osteoarticular TB treatment.

          Materials and methods

          Herein, we report a novel anti-TB dual delivery system based on rifapentine polylactic acid microspheres (RPMs) to treat infections, with the addition of adipose-derived mesenchymal stem cells (ASCs) seeded in hydroxyapatite/tricalcium phosphate (HA/TCP) to promote bone formation. Cell proliferation, osteogenesis, and apoptosis were performed to investigate the effects of rifapentine on ASCs. The RPMs were synthesized by emulsion-solvent evaporation method, and then the monolayer composite (ASC + RPM) and three-dimensional (3D) composite scaffold (ASC + RPM + HA/TCP) were constructed, respectively. The alkaline phosphatase (ALP) activity and real-time PCR were used for determining the osteogenic differentiation. The concentrations of rifapentine resulting from the composites were detected.


          The results showed that rifapentine has no influence on ASCs proliferation and osteogenesis when the drug concentration was below 20 µg/mL, which was significantly higher than minimal inhibitory concentration. The drug loading and encapsulation efficiency of RPMs were 40.56%±2.63% and 70.24%±2.18%, respectively. The proliferation of the cells in monolayer was higher than that in 3D composite, and the addition of RPMs slightly increased the proliferation. The ALP activity and gene expression of osteocalcin and osteopontin were higher in the 3D composite than those in the monolayer. Good biocompatibility was observed by microscopic image and H&E stain. The release tests revealed that the 3D composite exhibited sustained release profiles of rifapentine for 76 days. The dual delivery systems in 3D composite could moderate the burst release and extend the length of release time when compared to single delivery in monolayers.


          In conclusion, such dual delivery antituberculotic scaffold represents a potential new strategy for TB infections and bone defects.

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          Most cited references 23

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          Extrapulmonary tuberculosis: an overview.

          In the 1980s, after a steady decline during preceding decades, there was a resurgence in the rate of tuberculosis in the United States that coincided with the acquired immunodeficiency syndrome epidemic. Disease patterns since have changed, with a higher incidence of disseminated and extrapulmonary disease now found. Extrapulmonary sites of infection commonly include lymph nodes, pleura, and osteoarticular areas, although any organ can be involved. The diagnosis of extrapulmonary tuberculosis can be elusive, necessitating a high index of suspicion. Physicians should obtain a thorough history focusing on risk behaviors for human immunodeficiency virus (HIV) infection and tuberculosis. Antituberculous therapy can minimize morbidity and mortality but may need to be initiated empirically. A negative smear for acid-fast bacillus, a lack of granulomas on histopathology, and failure to culture Mycobacterium tuberculosis do not exclude the diagnosis. Novel diagnostic modalities such as adenosine deaminase levels and polymerase chain reaction can be useful in certain forms of extrapulmonary tuberculosis. In general, the same regimens are used to treat pulmonary and extrapulmonary tuberculosis, and responses to antituberculous therapy are similar in patients with HIV infection and in those without. Treatment duration may need to be extended for central nervous system and skeletal tuberculosis, depending on drug resistance, and in patients who have a delayed or incomplete response. Adjunctive corticosteroids may be beneficial in patients with tuberculous meningitis, tuberculous pericarditis, or miliary tuberculosis with refractory hypoxemia.
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            Donor site morbidity after anterior iliac crest bone harvest for single-level anterior cervical discectomy and fusion.

            This retrospective, questionnaire-based investigation evaluated iliac crest bone graft (ICBG) site morbidity in patients having undergone a single-level anterior cervical discectomy and fusion (ACDF) procedure performed by a single surgeon (T.J.A.). To evaluate acute and chronic problems associated with anterior ICBG donation, particularly long-term functional outcomes and impairments caused by graft donation. Anterior cervical discectomy and fusion procedures frequently use autologous anterior ICBG to facilitate osseous union. Although autologous ICBG offers several advantages over alternative grafting materials, donor site morbidity can be significant. Acute and chronic complications of donor sites have been reported, yet there are currently no reports of long-term functional outcomes after autologous anterior ICBG donation after single-level ACDF. A questionnaire was mailed to 187 consecutive patients who were retrospectively identified to have undergone autologous anterior ICBG harvest for single-level ACDF between 1994 and 1998. The questionnaire divided items into symptomatic (acute and chronic) and functional assessments. Patients answered yes, no, or not applicable; pain was assessed with a Visual Analogue Scale (VAS). Surveys were completed either by mail or follow-up telephone interview by 134 patients (71.6%). Average follow-up was 48 months (range, 24-72 months). Acute symptoms were reported at the following rates: ambulation difficulty, 50.7%; extended antibiotic usage, 7.5%; persistent drainage, 3.7%; wound dehiscence, 2.2%; and incision and drainage, 1.5%. The chronic symptom questionnaire demonstrated a high degree of satisfaction with the cosmetic result (92.5%). Pain at the donor site was reported by 26.1% of patients with a mean VAS score of 3.8 in 10, and 11.2% chronically use pain medication. Twenty-one patients (15.7%) reported abnormal sensations at the donor site, but only 5.2% reported discomfort with clothing. A unique functional assessment revealed current impairments at the following rates: ambulation, 12.7%; recreational activities, 11.9%; work activities, 9.7%; activities of daily living, 8.2%; sexual activity, 7.5%; and household chores, 6.7%. A large percentage of patients report chronic donor site pain after anterior ICBG donation, even when only a single-level ACDF procedure is performed. Moreover, long-term functional impairment can also be significant. Patients should be counseled regarding these potential problems, and alternative sources of graft material should be considered.
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              Tuberculosis of the spine: a review.

              We analyzed 124 papers published in the English language literature to define the indications and timing of surgery in spinal TB and to evaluate the outcome of various surgical procedures for kyphosis and neural outcome. Surgery in spinal tuberculosis is indicated for diagnostic dilemma, neural complications, and prevention of kyphosis progression. Up to 76% canal encroachment is compatible with a normal neurologic state as the spinal cord tolerates gradually developing compression. Patients with relatively preserved cord size, but with edema/myelitis and predominantly fluid compression on MRI respond well to nonoperative treatment. We believe patients with extradural compression by granulation tissue with little fluid component compressing or constricting the cord circumferentially with cord edema/myelitis or myelomalacia need early surgical decompression. Transthoracic transpleural anterior decompression and extrapleural anterolateral decompression have similar results in the dorsal spine. Instrumented stabilization helps prevent graft-related complications when postdébridement defects exceed two disc spaces (4-5 cm). Progression of kyphosis may occur in a short-segment disease despite instrumented stabilization. Its outcome in a long-segment disease needs observation. The correction of healed kyphosis requires multistage surgery and is fraught with complications. Prospective studies are needed to define surgical approach, steps, stages, problems, and obstacles to correct severe kyphosis in spinal TB.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                18 January 2019
                : 13
                : 373-384
                Department of Orthopaedics, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, China, 811789561@ 123456qq.com
                Author notes
                Correspondence: Xinghua Song, Department of Orthopaedics, The First Affiliated Hospital of Xinjiang Medical University, No 137, Liyushan South Road, Urumqi 830054, Xinjiang, China, Email 811789561@ 123456qq.com
                © 2019 Liang et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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