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.

Total intravenous anesthesia for geriatric hip fracture with severe systemic disease.

PURPOSE: Our study aimed to determine the impact of a novel technique of anesthesia administration on the clinical outcomes and complications in geriatric patients with severe systemic disease undergoing hip surgery. METHODS: We retrospectively identified patients aged > 65 years with severe systemic disease that was a constant of life [American Society of Anesthesiologists (ASA) IV] who underwent surgery for hip fracture between January 2018 and January 2020. The patients were divided into two groups: Group I [fascia iliaca compartment block plus propofol-based total intravenous anesthesia (FICB + TIVA)] and Group II [general anesthesia (GA)]. The primary outcomes were 30-day and 1-year mortality. The secondary outcomes included length of hospital stay, length of intensive care unit (ICU) stay, postoperative morbidity, Visual Analog Scale score, and consumption of analgesics. RESULTS: There was no significant difference in the 30-day mortality (5 vs. 3.8%, p = 0.85) and 1-year mortality (15 vs. 12%, p = 0.73) between the groups. Group I had significantly lower ICU requirements (p = 0.01) and shorter lengths of ICU stay (p < 0.001) and hospital stay (p < 0.001). Moreover, a smaller proportion of patients in Group I required postoperative morphine or oral opiates. CONCLUSION: Geriatric patients who underwent hip surgery under FICB + TIVA required fewer ICU admissions, shorter lengths of ICU and hospital stay, and had lesser postoperative opioid consumption than those who were under GA. Hence, we recommend the novel FICB + TIVA technique for hip fracture surgery in geriatric patients with poor general health status and high surgical risks (ASA IV).

The posterior capsule is distended in dysplastic hips, but the anterior capsule is not.

PURPOSE: In the setting of acetabular dysplasia, the increased translational motion of the femur may damage the labrum and cartilage, as well as stretch the capsule. The purpose of the study was to investigate the relationship between the acetabular coverage and the capsular stiffness by assessing the distension of anterior and posterior joint recesses on the hip computed tomography arthrography. METHODS: One hundred thirty-three patients (138 hips) with a median age of 36 years (range 18-50 years) who received the computed tomography arthrography for evaluation of nonarthritic hip pain in our institute between 2015 and 2017 were retrospectively reviewed. The maximal distance between the anterior/posterior capsule and the anterior femoral head-neck junction/posterior femoral head on the axial imaging of computed tomography arthrography was defined as the width of anterior/posterior joint recess. The width of anterior/posterior joint recess was adjusted with the diameter of the femoral head and was then compared between acetabular dysplasia (lateral center-edge angle < 25°), normal acetabulum (lateral center-edge angle between 25 and 39°), and deep acetabulum (lateral center-edge angle > 39°). In addition, the standard univariate linear regression analysis was used to investigate the relationship between the adjusted width of anterior/posterior joint recess and anterior/posterior coverage of the hip, determined by the anterior/posterior wall index. RESULTS: The adjusted width of posterior joint recess was significantly greater in the acetabular dysplasia group than the normal acetabulum and deep acetabulum groups (p < 0.01 and p = 0.02, respectively). There was no significant difference of the adjusted width of anterior joint recess between the groups (n.s.). The adjusted width of posterior joint recess had a significant but weak negative correlation with the anterior wall index (r = - 0.25, p < 0.001), and no correlation with the posterior wall index (r = - 0.0004, n.s.). There was no significant correlation between the adjusted width of anterior joint recess and the anterior/posterior wall index (r = 0.05, n.s./r = 0.07, n.s.). CONCLUSIONS: The distension of posterior capsule on the computed tomography arthrography was significantly greater in acetabular dysplasia. In addition, there was a significant but weak negative correlation between the distension of posterior capsule and the anterior coverage of the hip. It indicated a looser posterior capsule was observed in a dysplastic hip. The relevance of posterior capsular laxity to clinical outcomes warrants further investigation. Given the fact that the distension of anterior capsule was not significantly higher in acetabular dysplasia, the need of anterior capsular plication in a dysplastic hip should be carefully evaluated. LEVEL OF EVIDENCE: Level III.

Post-operative prophylactic antibiotics in aseptic revision hip and knee arthroplasty: a propensity score matching analysis.

The use of extended antibiotic (EA) prophylaxis (> 24 h) remains controversial in aseptic revision arthroplasty. We sought to determine whether EA prophylaxis reduces the risk of periprosthetic joint infection (PJI) in aseptic revision hip and knee arthroplasty. A total of 2800 patients undergoing aseptic revision hip and knee arthroplasty at five institutional databases from 2008 to 2017 were evaluated. One to two nearest-neighbor propensity score matching analysis was conducted between patients who did and did not receive extended antibiotic prophylaxis. The matching elements included age, sex, body mass index, Charlson comorbidity index, hospital distribution, year of surgery, joint (hip or knee), surgical time, CRP, preoperative hemoglobin, albumin, and length of stay. The primary outcome was the development of PJI, which was assessed at 30 days, 90 days, and 1 year following revision and analyzed separately. A total of 2467 (88%) patients received EA prophylaxis, and 333 (12%) patients received standard antibiotic (SA) prophylaxis (≤ 24 h). In the propensity-matched analysis, there was no difference between patients who received EA prophylaxis and those who did not in terms of 30-day PJI (0.3% vs. 0.3%, p = 1.00), 90-day PJI (1.7% vs. 2.1%, p = 0.62) and 1- year PJI (3.8% vs. 6.0%, p = 0.109). For revision hip, the incidence of PJI was 0.2% vs 0% at 30 days (p = 0.482), 1.6% vs 1.4% at 90 days (p = 0.837), and 3.4% vs 5.1% at 1 year (p = 0.305) in the EA and SA group. For revision knee, the incidence of PJI was 0.4% vs 0.9% at 30 days (p = 0.63), 1.8% vs 3.4% at 90 days (p = 0.331), and 4.4% vs 7.8% at 1 year (p = 0.203) in the EA and SA group. A post hoc power analysis revealed an adequate sample size with a beta value of 83%. In addition, the risks of Clostridium difficile and resistant organism infection were not increased. This multi-institutional study demonstrated no difference in the rate of PJIs between patients who received extended antibiotic prophylaxis and those who did not in aseptic revision arthroplasty. The risk of C. difficile and resistant organism infection was not increased with prolonged antibiotic use.

Total hip arthroplasty has higher complication rates in stiff spine patients: a systematic review and network meta-analysis.

BACKGROUND: Ankylosing spondylitis (AS) and spinal fusion (SF) classified as stiff spines have been associated with the increased rate of complications following total hip arthroplasty (THA). However, the differences between the two cohorts have inconsistent evidence. METHODS: We searched for studies comparing complications among stiff spine patients, including SF and AS, who underwent THA in PubMed/MEDLINE, Embase, Cochrane CENTRAL, Web of Science, and Scopus until March 2021. Studies detailing rates of mechanical complications, aseptic loosening, dislocation, infection, and revisions were included. We performed network meta-analyses using frequentist random-effects models to compare differences between cohorts. We used P-score to rank the better exposure with the lowest complications. RESULTS: Fourteen studies were included in the final analysis. A total of 740,042 patients were included in the systematic review and network meta-analysis. Mechanical complications were highest among SF patients (OR 2.33, 95% CI 1.86, 2.92, p < 0.05), followed by AS patients (OR 1.18, 95% CI 0.87, 1.61, p = 0.82) compared to controls. Long Spinal Fusions had the highest aseptic loosening (OR 2.33, 95% CI 1.83, 2.95, p < 0.05), dislocations (OR 3.25, 95% CI 2.58, 4.10, p < 0.05), infections (OR 2.14, 95% CI 1.73, 2.65, p < 0.05), and revisions (OR 5.25, 95% CI 2.23, 12.32, p < 0.05) compared to AS and controls. Our results suggested that SF with longer constructs may be associated with higher complications in THA patients. CONCLUSIONS: THAs following SFs have higher mechanical complications, aseptic loosening, dislocations, and infections, especially with longer constructs. AS patients may have fewer complications compared to this cohort.

Engineered periosteum-bone biomimetic bone graft enhances posterolateral spine fusion in a rabbit model.

BACKGROUND CONTEXT: Bone marrow derived mesenchymal stem cells (BMSCs) and periosteum-derived cells (PDCs) have shown great viability in terms of osteogenic potential and have been considered the major cellular source for skeletal tissue engineering. Using a PDCs-impregnated cell sheet to surround a BMSCs-impregnated tricalcium phosphate (TCP) scaffold might create a periosteum-bone biomimetic bone graft substitute to enhance spine fusion. PURPOSE: The purpose of this study was to determine the feasibility of using this newly tissue-engineered biomimetic bone graft for posterolateral spine fusion. STUDY DESIGN/SETTING: This study design was based on an animal model using adult male New Zealand White rabbits. METHODS: New Zealand White rabbits underwent operation and were divided into three groups based on the experimental material implanted in the bilateral L4-L5 intertransverse space. Group 1 was BMSCs-free TCP wrapped in a PDCs-free cell sheet. Group 2 was BMSCs-loaded-TCP wrapped in a PDCs-free cell sheet. Group 3 was BMSCs-loaded-TCP wrapped in a PDCs-loaded cell sheet. After 12 weeks, six rabbits from each group were euthanized for computed tomography scanning, manual palpation, biomechanical testing, and histology. Each group had 12 radiographic fusion areas for analysis because the right and left intertransverse fusion areas were collected separately. RESULTS: Radiographic union of 12 fusion areas for groups 1, 2, and 3 was 0, 3, and 9, respectively. Group 3 had significantly higher fusion success than groups 1 and 2 (p<.001). Solid fusion of six fusion segments in each group by manual palpation was 0, 1, and 5, accordingly. Group 3 had a higher successful solid fusion rate than groups 1 and 2 (p=.005). The average maximal torques at failure were 727±136 N mm, 627±91 N mm, and 882±195 N mm for groups 1, 2, and 3, accordingly. The maximal torque was significantly higher in group 3 than in group 2 (p=.028). Histological evaluation verified that new bone regeneration were greater in the group 3 samples. CONCLUSIONS: The results indicated the potential of using a PDCs-impregnated cell sheet to surround the BMSCs-impregnated TCP scaffold for creating a periosteum-bone biomimetic bone graft substitute to enhance bone regeneration and posterolateral fusion success.

Avascular Necrosis of Bone following Chemotherapy in Cancer Patients with Coagulopathy: Report of Two Cases.

We report 2 cases of patients with solid tumors and coagulopathy who experienced avascular necrosis (AVN) of the bone following chemotherapy. Both cases exhibited nontraumatic bilateral AVN of the femoral heads, and one also showed bilateral AVN of the humeral heads. One case had multiple thromboembolic complications, including pulmonary obstructive syndrome and paraneoplastic pain. The other showed multiple paraneoplastic syndromes, with hypercalcemia and thrombocytosis. Groin pain and claudication of the lower extremities developed and persisted. Both patients eventually received bilateral hip arthroplasty due to AVN of both femoral heads.

Sustained Delivery of Analgesic and Antimicrobial Agents to Knee Joint by Direct Injections of Electrosprayed Multipharmaceutical-Loaded Nano/Microparticles.

In this study, we developed biodegradable lidocaine⁻/vancomycin⁻/ceftazidime⁻eluting poly(d,l⁻lactide⁻co⁻glycolide) (PLGA) nano/microparticulate carriers using an electrospraying process, and we evaluated the release behaviors of the carriers in knee joints. To prepare the particles, predetermined weight percentages of PLGA, vancomycin, ceftazidime, and lidocaine were dissolved in solvents. The PLGA/antibiotic/lidocaine solutions were then fed into a syringe for electrospraying. After electrospraying, the morphology of the sprayed nano/microparticles was elucidated by scanning electron microscopy (SEM). The in vitro antibiotic/analgesic release characteristics of the nano/microparticles were studied using high-performance liquid chromatography (HPLC). In addition, drug release to the synovial tissues and fluids was studied in vivo by injecting drug-loaded nano/microparticles into the knee joints of rabbits. The biodegradable electrosprayed nano/microparticles released high concentrations of vancomycin/ceftazidime (well above the minimum inhibition concentration) and lidocaine into the knee joints for more than 2 weeks and for over 3 days, respectively. Such results suggest that electrosprayed biodegradable nano/microcarriers could be used for the long-term local delivery of various pharmaceuticals.

Nanofibers used for delivery of antimicrobial agents.

Nanotechnology has gained an increased interest in several different areas of biotechnology including the drug delivery via nanofibers. Self-assembly, phase separation and electrospinning can all be used to successfully generate nanofibers with sizes well within the range of those of the fibers present in the native extracellular matrix (50-500 nm). In this article, the authors introduced the most popular applications of nanofibers related to the delivery of antimicrobial agents for infectious diseases. To date, only a few in-vivo studies are available at present to demonstrate its clinical potential; most of the studies are of exploratory nature and rely mostly on in-vitro experiments. Therefore, further advancement in the production and clinical performance of drug-loaded nanofibrous matrices seems necessary.

Biodegradable drug-eluting nanofiber-enveloped implants for sustained release of high bactericidal concentrations of vancomycin and ceftazidime: in vitro and in vivo studies.

We developed biodegradable drug-eluting nanofiber-enveloped implants that provided sustained release of vancomycin and ceftazidime. To prepare the biodegradable nanofibrous membranes, poly(D,L)-lactide-co-glycolide and the antibiotics were first dissolved in 1,1,1,3,3,3-hexafluoro-2-propanol. They were electrospun into biodegradable drug-eluting membranes, which were then enveloped on the surface of stainless plates. An elution method and a high-performance liquid chromatography assay were employed to characterize the in vivo and in vitro release rates of the antibiotics from the nanofiber-enveloped plates. The results showed that the biodegradable nanofiber-enveloped plates released high concentrations of vancomycin and ceftazidime (well above the minimum inhibitory concentration) for more than 3 and 8 weeks in vitro and in vivo, respectively. A bacterial inhibition test was carried out to determine the relative activity of the released antibiotics. The bioactivity ranged from 25% to 100%. In addition, the serum creatinine level remained within the normal range, suggesting that the high vancomycin concentration did not affect renal function. By adopting the electrospinning technique, we will be able to manufacture biodegradable drug-eluting implants for the long-term drug delivery of different antibiotics.

Preclinical experiments on the release behavior of biodegradable nanofibrous multipharmaceutical membranes in a model of four-wall intrabony defect.

Guided tissue regeneration (GTR) therapy has been widely used to regenerate lost periodontium from periodontal disease. However, in terms of regenerative periodontal therapy, a multidrug-loaded biodegradable carrier can be even more promising in dealing with periodontal disease. In the current study, we fabricated biodegradable nanofibrous collagen membranes that were loaded with amoxicillin, metronidazole, and lidocaine by an electrospinning technique. The in vitro release behavior and the cytotoxicity of the membranes were investigated. A four-wall intrabony defect was created in rabbits for in vivo release analysis. The bioactivity of the released antibiotics was also examined. The experimental results showed that the drug-loaded collagen membranes could provide sustainable release of effective amoxicillin, metronidazole, and lidocaine for 28, 56, and 8 days, respectively, in vivo. Furthermore, the bioactivity of the released antibiotics remained high, with average bioactivities of 50.5% for amoxicillin against Staphylococcus aureus and 58.6% for metronidazole against Escherichia coli. The biodegradable nanofibrous multipharmaceutical membranes developed in this study may provide a promising solution for regenerative periodontal therapy.

Novel biodegradable sandwich-structured nanofibrous drug-eluting membranes for repair of infected wounds: an in vitro and in vivo study.

BACKGROUND: The purpose of this study was to develop novel sandwich-structured nanofibrous membranes to provide sustained-release delivery of vancomycin, gentamicin, and lidocaine for repair of infected wounds. METHODS: To prepare the biodegradable membranes, poly(D, L)-lactide-co-glycolide (PLGA), collagen, and various pharmaceuticals, including vancomycin, gentamicin, and lidocaine, were first dissolved in 1,1,1,3,3,3-hexafluoro-2-propanol. They were electrospun into sandwich-structured membranes with PLGA/collagen as the surface layers and PLGA/drugs as the core. An elution method and a high-pressure liquid chromatography assay were used to characterize in vivo and in vitro drug release from the membranes. In addition, repair of infected wounds in rats was studied. Histological examination of epithelialization and granulation at the wound site was also performed. RESULTS: The biodegradable nanofibrous membranes released large amounts of vancomycin and gentamicin (well above the minimum inhibition concentration) and lidocaine in vivo for more than 3 weeks. A bacterial inhibition test was carried out to determine the relative activity of the antibiotics released. The bioactivity ranged from 40% to 100%. The nanofibrous membranes were functionally active in treating infected wounds, and were very effective as accelerators in early-stage wound healing. CONCLUSION: Using the electrospinning technique, we will be able to manufacture biodegradable, biomimetic, nanofibrous, extracellular membranes for long-term delivery of various drugs.