Preclinical Animal Study and Pilot Clinical Trial of Using Enriched Peripheral Blood-Derived Mononuclear Cells for Intervertebral Disc Degeneration.

Low back pain (LBP) is a leading cause of long-term disability globally. Intervertebral disk degeneration (IVDD) is mainly responsible for discogenic pain in LBP-affected young patients. There is no effective therapy to reverse disease severity and IVDD progression. This study investigates the effect of human peripheral blood-derived mononuclear cells (PBMCs) on pain relief and life quality improvement in IVDD patients. The enriched monocytes of the PBMCs could differentiate into CD14 and CD206 double-positive M2 macrophages in vitro. Preclinical evidence in rats showed that the transplanted PBMCs exhibited anti-inflammatory and moderate tissue-repair effects on controlling IVDD progress in the rat model. The PBMCs significantly steered the aggrecan and type II collagen expressions and attenuated the pro-inflammatory cytokines in the affected disk. Based on the animal results, 36 patients with chronic low back pain (CLBP) were included in clinical trials. The control group was conservative care only, and the experimental group was platelet-rich plasma (PRP) and PBMCs intradiscal injections. We first confirmed the single lumbar disk causing the discogenic pain by provocative discography or magnetic resonance imaging (MRI). Discogenic LBP participants received one intradiscal injection of autologous PBMCs and followed for 6 months. Our clinical trial showed that patients' LBP and disability were significantly ameliorated after the PBMCs transplantation rather than PRP. These preclinical and pilot clinical studies indicate that intradiscal injection of the enriched PBMCs might be a feasible and potential cell therapy to control pain and disability in IVDD patients.

Enriched Peripheral Blood-Derived Mononuclear Cells for Treating Knee Osteoarthritis.

Osteoarthritis (OA) is a common chronic skeletal disease in the elderly. There is no effective therapy to reverse disease severity and knee OA (KOA) progression, particularly at the late stage. This study aims to examine the effect of peripheral blood-derived mononuclear cells (PBMNCs) on pain and motor function rescue in patients with Kellgren-Lawrence (KL) grade II to IV KOA. Participants received one intra-articular (IA) injection of autologous PBMNCs. The mononuclear cells were isolated from peripheral blood, enriched by a specialized medium (MoFi medium), and separated by Ficoll-Paque solution. The isolated and enriched PBMNCs could differentiate into M1 and M2 macrophages in vitro. The in vivo anti-inflammatory effect of the PBMNCs was similar to that of bone marrow mesenchymal stem cells, evaluated by complete Freund's adjuvant-induced arthritis in rodents. A single-arm and open-label pilot study showed that patients' knee pain and motor dysfunction were significantly attenuated after the cell transplantation, assessed by visual analogue scale (VAS) and Knee injury and Osteoarthritis Outcome Score (KOOS) at 6 and 12 months post-treatment. Notably, the therapeutic effect of the PBMNCs treatment can be stably maintained for 24 months, as revealed by the KOOS scores. These preclinical and pilot clinical data suggest that IA injection of MoFi-PBMNCs might serve as a novel medical technology to control the pain and the progress of KOA.

Induction of type II collagen expression in M2 macrophages derived from peripheral blood mononuclear cells.

The human type II collagen (Col II), specifically expressed in chondrocytes, is a crucial component of the adult hyaline cartilage. We examine the potential of artificial induction of Col II in human peripheral blood mononuclear cells (PBMNCs) as a novel Col II provider. Human PBMNCs were purified and were treated with high doses of macrophage-colony stimulating factor (M-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), or granulocyte-colony stimulating factor (G-CSF) and examined the Col II expression at indicated days. Quantitative Col II expression was validated by real-time reverse transcriptase-polymerase chain reaction (RT-PCR), immunocytochemistry, and flow cytometry. We demonstrate that monocytes in PBMNCs can be artificially induced to express both Col II proteins and M2 macrophage markers by the high concentration of colony-stimulating factors, especially M-CSF and GM-CSF. The Col II proteins were detected on the cell membrane and in the cytoplasm by flow cytometry and immunocytostaining. Combination with IL-4 provided a synergistic effect with M-CSF/GM-CSF to trigger Col II expression in M2 macrophages. These CD206 and Col II double-expressing cells, named modified macrophages, share M2 macrophages' anti-inflammatory potency. We demonstrated that the modified macrophages could significantly attenuate the inflammatory progress of Complete Freund's adjuvant (CFA)-induced arthritis and collagen-induced arthritis in rodents. Here, we provide the first evidence that a modified macrophage population could ectopically express Col II and control the progress of arthritis in animals.

Surgical stabilization of the ipsilateral scapula and rib fractures using the mirror Judet approach: a preliminary result.

BACKGROUND: We report our preliminary results using a single approach, the mirror Judet approach, for patients with both ipsilateral scapula and multiple rib fractures. METHODS: Five consecutive patients [median age: 56 years (range: 44 ~ 60)] with ipsilateral scapula and multiple rib fractures that met the surgical indications were retrospectively reviewed. A single approach, the mirror Judet approach, was used for surgical stabilization of the scapula and targeted rib fractures. Thoracoscopic surgery was performed first for management of associated lung lesions and marking the targeted rib. All patients received the same rehabilitation protocol and a minimum 12-month follow-up. RESULTS: All surgically-fixed fractures eventually united without malunion. No complaints of intercostal neuralgia, infection, or other complications were seen. The mean range of motion in the injured shoulder returned to at least 90% of the contralateral side range. The mean Disabilities of the Arm, Shoulder, and Hand score at the 12th month was 2.0 (range: 0-7). All patients were able to return to their previous work. CONCLUSION: The mirror Judet approach allows for the surgical stabilization of the ipsilateral scapula and multiple rib fractures using the same approach and provides acceptable functional outcomes in well-selected patients. LEVEL OF EVIDENCE: Level IV.

Musculoskeletal injuries and management of victims from collapsed buildings in the 2016 Taiwan earthquake: Experiences in a tertiary medical center.

BACKGROUND: Previous studies have seldom focused on injury patterns, especially musculoskeletal injuries, caused by building collapse during earthquakes. The aim of this study was to investigate the musculoskeletal injury profiles and management of patients rescued from collapsed buildings in the 2016 Taiwan earthquake. METHODS: We conducted a retrospective study using the electronic medical record (EMR) system. We enrolled 31 patients rescued from specific collapsed buildings (the WJ group) and 56 patients injured in the same earthquake as a control group. We investigated the admission history, injury profile, treatment, and outcomes for these patients. RESULTS: The WJ group (51%) had significantly higher admission rates compared to the control group (25%) (p = 0.012). Although the odds ratio (OR) of fracture incidence was lower in the WJ group (OR: 0.79), there was a higher OR of multiple fractures (OR: 2.617) and axial skeletal fractures (OR: 2.893 for vertebral fracture, and OR: 1.893 ribs for rib fractures) in the WJ group. Among the 28 fracture patients, 9 (32.1%) underwent surgical interventions. A higher incidence of rhabdomyolysis was noted in the WJ group (OR: 34.73). Also, all 5 rhabdomyolysis cases combined with acute kidney injury were in the WJ group, and 1 of them required emergent hemodialysis for severe hyperkalemia. CONCLUSION: Patients extricated from collapsed buildings have a higher incidence of multiple fractures and axial skeletal fractures. More severe soft tissue injuries, including rhabdomyolysis and compartment syndrome, were also identified. The medical system should develop rescue and treatment strategies for this rare situation.

Aeromonas hydrophilia-infected nonunion of a closed tibial fracture in a healthy adolescent: A case report.

Aeromonas hydrophilia can cause soft tissue infection in both immunocompromised and healthy persons. A healthy 15-year-old adolescent fell into a ditch after a scooter accident and sustained a right distal tibial shaft closed fracture, a right femoral shaft closed fracture, and a dirty laceration over the medial aspect of the distal thigh above the right knee. After empiric antibiotics and radical debridement of the contaminated wound, a femoral interlocking nail and tibial external fixator were applied. However, acute osteomyelitis later presented in his femur and tibia, and Aeromonas hydrophilia grew in cultures from the knee wound and the fracture sites. During the follow-up, his tibia became an infected nonunion, and was successfully treated with the induced membrane technique. In an otherwise healthy patient with a closed fracture, Aeromonas hydrophilia can cause acute osteomyelitis and necrotizing fasciitis by spreading from a nearby contaminated wound. Exposure to water is a risk factor for Aeromonas hydrophilia infection.

Computational comparison of different plating strategies in medial open-wedge high tibial osteotomy with lateral hinge fractures.

BACKGROUND: Lateral hinge fracture (LHF) is associated with nonunion and plate breakage in high tibial osteotomy (HTO). Mechanical studies investigating fixation strategies for LHFs to restore stability and avoid plate breakage are absent. This study used computer simulation to compare mechanical stabilities in HTO for different LHFs fixed with medial and bilateral locking plates. METHODS: A finite element knee model was created with HTO and three types of LHF, namely T1, T2, and T3 fractures, based on the Takeuchi classification. Either medial plating or bilateral plating was used to fix the HTO with LHFs. Furthermore, the significance of the locking screw at the combi hole (D-hole) of the medial TomoFix plate was evaluated. RESULTS: The osteotomy gap shortening distance increased from 0.53 to 0.76, 0.79, and 0.72 mm after T1, T2, and T3 LHFs, respectively, with medial plating only. Bilateral plating could efficiently restore stability and maintain the osteotomy gap. Furthermore, using the D-hole screw reduced the peak stress on the medial plate by 28.7% (from 495 to 353 MPa), 26.6% (from 470 to 345 MPa), and 32.6% (from 454 to 306 MPa) in T1, T2, and T3 LHFs, respectively. CONCLUSION: Bilateral plating is a recommended strategy to restore HTO stability in LHFs. Furthermore, using a D-hole locking screw is strongly recommended to reduce the stress on the medial plate for lowering plate breakage risk.

Femoral Component Alignment with a New Extramedullary Femoral Cutting Guide Technique.

BACKGROUND: Intramedullary (IM) or extramedullary (EM) mechanical guides are used as alignment tools during total knee arthroplasty (TKA) surgery. The EM guide is less invasive; however, the IM mechanical guide is the preferred option since it has shown superior outcomes in several studies. Picture archive and communication system (PACS) images, if available, are extensively used for preoperative planning and intraoperative guidance. This retrospective study compared TKA outcomes using the conventional IM guide and a new EM technique which uses PACS image for preoperative and intraoperative assessment bone resection. To the best of our knowledge, this is the first study with the new EM technique. MATERIALS AND METHODS: The study was performed on 205 knees (190 patients) for TKA from 2011 to 2013. The perioperative blood loss and the postoperative alignment angles were assessed for both mechanical guides. The angles were measured on the radiographs of the patient. The blood loss was assessed by the blood accumulated in the hemovac drain during the surgery and until 3 days after the surgery. RESULTS: The new EM guide provided similar postoperative alignment as that obtained with the IM guide. CONCLUSION: The EM-guided method for femoral bone cutting using PACS films in TKA is as good as the IM method. The additional advantages of less injury to the bone and less fat emboli load to the cardiopulmonary system with the EM method makes it an attractive choice for routine, especially in the elderly and/or simultaneous bilateral, TKA in hospitals without modern computer-assisted navigation systems.

Brain tumor senescence might be mediated by downregulation of S-phase kinase-associated protein 2 via butylidenephthalide leading to decreased cell viability.

Developing an effective drug for treating human glioblastoma multiform (GBM) has been investigated persistently. A pure compound butylidenephthalide (BP), isolated from Angelica sinensis, has been shown the activities to arrest the growth and initiate apoptosis of GBM in our previous reports. In this study, we further demonstrated that BP treatment accelerates the cell senescence in a dose-dependent manner in vitro and in vivo. S-phase kinase-associated protein 2 (Skp2), a proto-oncogene, is generally upregulated in cancer. We found that it was downregulated in BP-treated GBM cells. The downregulation of Skp2 is parallel with increasing p16 and p21 expression which causes G0/G1 arrest and tumor cell senescence. We also found that restoring the Skp2 protein level by exogenous overexpression prevents the BP-induced cell senescence. Therefore, the linkage between cell senescence and Skp2 expression is strengthened. Promoter binding analysis further detailed that the BP-mediated SP1 reduction might involve in the Skp2 downregulation. In summary, these results emphasize that BP-triggered senescence in GBM cells is highly associated with its control on Skp2 regulation.