ABSTRACT
OBJECTIVE: Myocardial infarctions constitute a major factor contributing to non-natural mortality world-wide. Clinical trials of myocardial regenerative therapy, currently pursued by cardiac surgeons, involve administration of stem cells into the hearts of patients suffering from myocardial infarctions. Unfortunately, surgical acquisition of these cells from bone marrow or heart is traumatic, retention of these cells to sites of therapeutic interventions is low, and directed differentiation of these cells in situ into cardiomyocytes is difficult. The specific aims of this work were: (1) to generate autologous, human, pluripotent, induced stem cells (ahiPSCs) from the peripheral blood of the patients suffering myocardial infarctions; (2) to bioengineer heterospecific antibodies (htAbs) and use them for recruitment of the ahiPSCs to infarcted myocardium; (3) to initiate in situ directed cardiomyogenesis of the ahiPSCs retained to infarcted myocardium. METHODS: Peripheral blood was drawn from six patients scheduled for heart transplants. Mononuclear cells were isolated and reprogrammed, with plasmids carrying six genes (NANOG, POU5F1, SOX2, KLF4, LIN28A, MYC), to yield the ahiPSCs. Cardiac tissues were excised from the injured hearts of the patients, who received transplants during orthotopic surgery. These tissues were used to prepare in vitro models of stem cell therapy of infarcted myocardium. The htAbs were bioengineered, which simultaneously targeted receptors displayed on pluripotent stem cells (SSEA-4, SSEA-3, TRA-1-60, TRA-1-81) and proteins of myocardial sarcomeres (myosin, α-actinin, actin, titin). They were used to bridge the ahiPSCs to the infarcted myocardium. The retained ahiPSCs were directed with bone morphogenetic proteins and nicotinamides to differentiate towards myocardial lineage. RESULTS: The patients' mononuclear cells were efficiently reprogrammed into the ahiPSCs. These ahiPSCs were administered to infarcted myocardium in in vitro models. They were recruited to and retained at the treated myocardium with higher efficacy and specificity, if were preceded with the htAbs, than with isotype antibodies or plain buffers. The retained cells differentiated into cardiomyocytes. CONCLUSIONS: The proof of concept has been attained, for reprogramming the patients' blood mononuclear cells (PBMCs) into the ahiPSCs, recruiting these cells to infarcted myocardium, and initiating their cardiomyogenesis. This novel strategy is ready to support the ongoing clinical trials aimed at regeneration of infarcted myocardium.
ABSTRACT
PURPOSE: When the femoral stem was well fixed in patients with a deep prosthetic hip infection, the authors performed a two-stage revision procedure using antibiotic-loaded cement spacers (ALCS) without removal of the stem, and the efficacy of this treatment was assessed. MATERIALS AND METHODS: For 12 cases of infected hip arthroplasties, a two-stage procedure was performed, and the patients were followed up for over 2 years. After the acetabular component and head was removed, debridement was done. The molded ALCS was inserted. Revision was then performed after eradication of the infection. The results were analyzed, including the changes in the clinical manifestation, the radiologic findings, the laboratory results, the functional score and the complications. RESULTS: Of all 12 cases, the two-stage revision arthroplasty using an ALCS with retention of the stem was performed in 11 cases (92%), on an average of 66 days (range: 40~152 days). In the 11 revised cases, there was no evidence of recurrence of infection. In the 11 cases, the mean Harris hip score improved from 40.1 points preoperatively to 91.8 points at last the follow-up. The mean WOMAC score improved from 41.8 points preoperatively to 81 points at the last follow-up. The mean Harris hip score was 85.3 points and the WOMAC score was 72.4 points during the ALCS insertion-period. CONCLUSION: For the case of a perioprosthetic hip infection with a well-fixed femoral stem, two-staged revision using an ALCS without stem removal could be an alternative method in terms of effective infection control and preservation of the joint function.
