Michael J Yaszemski

Mayo Foundation for Medical Education and Research, Рочестер, Michigan, United States

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Publications (211)817.53 Total impact

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    ABSTRACT: There is a need to improve the prediction of fracture risk for patients with metastatic bone disease. CT-based rigidity analysis (CTRA) is a sensitive and specific method, yet its influence on clinical decision-making has never been quantified. What is the influence of CTRA on providers' perceived risk of fracture? (2) What is the influence of CTRA on providers' treatment recommendations in simulated clinical scenarios of metastatic bone disease of the femur? (3) Does CTRA improve interobserver agreement regarding treatment recommendations? We conducted a survey among 80 academic physicians (orthopaedic oncologists, musculoskeletal radiologists, and radiation oncologists) using simulated vignettes of femoral lesions presented as three separate scenarios: (1) no CTRA input (baseline); (2) CTRA input suggesting increased risk of fracture (CTRA+); and (3) CTRA input suggesting decreased risk of fracture (CTRA-). Participants were asked to rate the patient's risk of fracture on a scale of 0% to 100% and to provide a treatment recommendation. Overall response rate was 62.5% (50 of 80). When CTRA suggested an increased risk of fracture, physicians perceived the fracture risk to be slightly greater (37% ± 3% versus 42% ± 3%, p < 0.001; mean difference [95% confidence interval {CI}] = 5% [4.7%-5.2%]) and were more prone to recommend surgical stabilization (46% ± 9% versus 54% ± 9%, p < 0.001; mean difference [95% CI] = 9% [7.9-10.1]). When CTRA suggested a decreased risk of fracture, physicians perceived the risk to be slightly decreased (37% ± 25% versus 35% ± 25%, p = 0.04; mean difference [95% CI] = 2% [2.74%-2.26%]) and were less prone to recommend surgical stabilization (46% ± 9% versus 42% ± 9%, p < 0.03; mean difference [95% CI] = 4% [3.9-5.1]). The effect size of the influence of CTRA on physicians' perception of fracture risk and treatment planning varied with lesion severity and specialty of the responders. CTRA did not increase interobserver agreement regarding treatment recommendations when compared with the baseline scenario (κ = 0.41 versus κ = 0.43, respectively). Based on this survey study, CTRA had a small influence on perceived fracture risk and treatment recommendations and did not increase interobserver agreement. Further work is required to properly introduce this technique to physicians involved in the care of patients with metastatic lesions. Given the number of preclinical and clinical studies outlining the efficacy of this technique, better education through presentations at seminars/webinars and symposia will be the first step. This should be followed by clinical trials to establish CTRA-based clinical guidelines based on evidence-based medicine. Increased exposure of clinicians to CTRA, including its underlying methodology to study bone structural characteristics, may establish CTRA as a uniform guideline to assess fracture risk. Level III, economic and decision analyses.
    Clinical Orthopaedics and Related Research 05/2015; DOI:10.1007/s11999-015-4371-1 · 2.88 Impact Factor
  • Xifeng Liu, Alan L. Miller, Michael J. Yaszemski, Lichun Lu
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    ABSTRACT: Novel biodegradable and crosslinkable copolymers of hydrophobic poly(propylene fumarate)-co-poly(lactic-co-glycolic acid) (PPF-PLGA) linked with hydrophilic poly(ethylene glycol) (PEG), namely PPF-PLGA-PEG, were developed and fabricated into core-shell nanoparticles through self-assembly and photocrosslinking. A fluorescent probe, rhodamine B (RhB), was conjugated to the end of the copolymer chain (PPF-PLGA-PEG-RhB), which allows tracking of the nanoparticles through visualizing the fluorescence probe. Folic acid (FA) ligand was conjugated to another series of chains (PPF-PLGA-PEG-FA) for targeted delivery of the nanoparticles to the tumor sites by binding to the ubiquitously overexpressed FA receptors on tumor cells. Our results showed that PPF-PLGA-PEG nanoparticles incorporated with RhB fluorescence probes and FA tumor binding ligands have specific cancer cell targeting and imaging abilities. These crosslinkable nanoparticles are potentially useful to serve as a platform for conjugation of fluorescence probes as well as various antibodies and peptides for cancer targeted imaging or drug delivery.
    RSC Advances 04/2015; 5(42). DOI:10.1039/C5RA04096E · 3.71 Impact Factor
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    ABSTRACT: Background: Pathological fractures could be prevented if reliable methods of fracture risk assessment were available. A multi-center, prospective study was conducted to identify significant predictors of physicians' treatment plan for skeletal metastasis based on clinical fracture risk assessments and the proposed CT-based Rigidity Analysis (CTRA). Methods: Orthopaedic oncologists selected a treatment plan for 124 patients with 149 metastatic lesions based on Mirels method. Then, CTRA was performed and the results were provided to the physicians, who were asked to reassess their treatment plan. The pre- and post-CTRA treatment plans were compared to identify cases where the treatment plan was changed based on the CTRA report. Patients were followed for a 4 month period to establish the incidence of pathological fractures. Results: Pain, lesion type and lesion size were significant predictors of the pre-CTRA plan. After providing the CTRA results, physicians changed their plan for 36 patients. CTRA results, pain and primary source of metastasis were significant predictors of the post-CTRA plan. Follow up of patients who did not undergo fixation resulted in 7 fractures; CTRA predicted these fractures with 100% sensitivity and 90% specificity, whereas the Mirels method was 71% sensitive and 50% specific. Conclusions: Lesion type and size and pain level influenced the physicians' plans for management of metastatic lesions. Physicians' treatment plans and fracture risk predictions were significantly influenced by the availability of CTRA results. Due to its high sensitivity and specificity. CTRA could potentially be used as a screening method for pathological fractures. Copyright © 2015, American Association for Cancer Research.
    Clinical Cancer Research 02/2015; 21(11). DOI:10.1158/1078-0432.CCR-14-2668 · 8.19 Impact Factor
  • RSC Advances 02/2015; DOI:10.1039/C5RA00508F · 3.71 Impact Factor
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    ABSTRACT: The “Workshop on Standards & Measurements for Tissue Engineering Scaffolds” was held on May 21, 2013 in Indianapolis, IN, and was sponsored by the ASTM International (ASTM). The purpose of the workshop was to identify the highest priority items for future standards work for scaffolds used in the development and manufacture of tissue engineered medical products (TEMPs). Eighteen speakers and 78 attendees met to assess current scaffold standards and to prioritize needs for future standards. A key finding was that the ASTM TEMPs subcommittees (F04.41-46) have many active “guide” documents for educational purposes, but few standard “test methods” or “practices.” Overwhelmingly, the most clearly identified need was standards for measuring the structure of scaffolds, followed by standards for biological characterization, including in vitro testing, animal models and cell-material interactions. The third most pressing need was to develop standards for assessing the mechanical properties of scaffolds. Additional needs included standards for assessing scaffold degradation, clinical outcomes with scaffolds, effects of sterilization on scaffolds, scaffold composition, and drug release from scaffolds. Discussions highlighted the need for additional scaffold reference materials and the need to use them for measurement traceability. Workshop participants emphasized the need to promote the use of standards in scaffold fabrication, characterization, and commercialization. Finally, participants noted that standards would be more broadly accepted if their impact in the TEMPs community could be quantified. Many scaffold standard needs have been identified and focus is turning to generating these standards to support the use of scaffolds in TEMPs. © 2014 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2014.
    Journal of Biomedical Materials Research Part B Applied Biomaterials 09/2014; DOI:10.1002/jbm.b.33286 · 2.33 Impact Factor
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    ABSTRACT: Study Design. Vertebral fracture load and stiffness from a metastatic vertebral defect model were predicted using nonlinear finite element models (FEM) and validated experimentally.Objective. The study objective was to develop and validate an FEM-based tool for predicting polymer-augmented lytic vertebral fracture load and stiffness and the influence of metastatic filling materials.Summary of Background Data. Percutaneous vertebroplasty has the potential to reduce vertebral fracture risk affected with lytic metastases by providing mechanical stabilization. However, it has been shown that the mismatch in mechanical properties between poly(methyl-methacrylate) (PMMA) and bone induces secondary fractures and intervertebral disc degeneration. A biodegradable co-polymer, poly(propylene fumarate-co-caprolactone) [P(PF-co-CL)], has been shown to possess the appropriate mechanical properties for bone defect repair.Methods. Simulated metastatic lytic defects were created in 40 cadaveric vertebral bodies, which were randomized into four groups: intact vertebral body (Intact), simulated defect without treatment (Negative), defect treated with P(PF-co-CL) (Co-polymer), and defect treated with PMMA (PMMA). Spines were imaged with quantitative computerized tomography (QCT), and QCT/FEM-subject-specific, non-linear models were created. Predicted fracture loads and stiffness were identified and compared to experimentally measured values using Pearson's correlation analysis and paired t-test.Results. There was no significant difference between the measured and predicted fracture loads and stiffness for each group. Predicted fracture loads were larger for PMMA-augmentation (3960 N (1371 N)) compared to that of the co-polymer, negative and intact groups (3484 N (1497 N), 3237 N (1744 N) and 1747 N (702 N)). A similar trend was observed in the predicted stiffness. Moreover, predicted and experimental fracture loads were strongly correlated (R = 0.78), while stiffness showed moderate correlation (R = 0.39).Conclusion. QCT/FEM was successful for predicting fracture loads of metastatic, polymer-augmented vertebral bodies. Overall, we have demonstrated that QCT/FEM may be a useful tool for predicting in situ vertebral fracture load resulting from vertebroplasty.
    Spine 07/2014; 39(22). DOI:10.1097/BRS.0000000000000540 · 2.45 Impact Factor
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    ABSTRACT: Biphenotypic sinonasal sarcoma (SNS) is a newly described tumor of the nasal and paranasal areas. Here we report a recurrent chromosomal translocation in SNS, t(2;4)(q35;q31.1), resulting in a PAX3-MAML3 fusion protein that is a potent transcriptional activator of PAX3 response elements. The SNS phenotype is characterized by aberrant expression of genes involved in neuroectodermal and myogenic differentiation, closely simulating the developmental roles of PAX3.
    Nature Genetics 05/2014; 46(7). DOI:10.1038/ng.2989 · 29.65 Impact Factor
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    ABSTRACT: This is a technical note of pelvic reconstruction performed by an advanced multidisciplinary team. The authors report a new 3-stage reconstruction of the hemipelvis after Type 3 sacrectomy involving instrumented spinoiliac arthrodesis and pedicled fibula grafting in 2 patients. The anterior stage of the procedure begins with a transabdominal approach to mobilize the viscera and to free up the tumor from the vessels. The posterior divisions of internal iliac vessels, the middle sacral vessels, and the lateral sacral vessels are then ligated. An anterior vertebrectomy is done at the appropriate level, followed by an anterior osteotomy through the lateral planed surgical margin of the sacrum close to the salvaged sacroiliac joint. The second stage includes a major sacral resection with lower-extremity amputation from the pubic symphysis through the intact side of the sacrum, ipsilateral pedicled fibula harvesting, and closure with an ipsilateral pedicled quadriceps flap. The final stage involves reconstruction with lumboiliac instrumentation. The pedicled fibular graft left from the second stage is then placed distally within the previously created iliopectineal docking site and proximally within the L-5 docking site. The authors believe that this is a feasible and reproducible technique with theoretical advantages that have to be proved in the long-term follow-up.
    Journal of neurosurgery. Spine 04/2014; 21(2). DOI:10.3171/2014.1.SPINE13245 · 2.36 Impact Factor
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    ABSTRACT: Traumatic injuries occurring at the conus medullaris of the spinal cord cause both permanent damage to the central nervous system, and to the cauda equina nerve roots. This proof of concept study determined whether implanting the nerve roots into a biodegradable scaffold would improve regeneration after injury. All experimental work involving rats was performed according to approved guidelines by the Mayo Clinic Institutional Animal Care and Use Committee (IACUC). Surgical procedures were performed on 32 Sprague Dawley rats. Four ventral cauda equina nerve roots were re-implanted either directly into the ventral cord stump or through a poly(lactic-co-glycolic acid) (PLGA) scaffold. These experimental groups were compared to a control group in which the nerves were inserted into a muscle fascia barrier that was placed between the spinal cord and nerve roots. Animals were sacrificed at four weeks. This work was funded by the authors' institution; Morton Cure Paralysis Fund; The Craig H. Neilsen Foundation; and NIBIB grant R01 EB 02390. There was no conflict of interest between the study funding and the conclusions drawn. There was no difference in motor neuron counts in the spinal cord rostral to the injury in all treatment groups, implying equal potential for regeneration into implanted nerve roots. One-way ANOVA testing, with Tukey's post-test, showed a statistically significant improvement in axon regeneration through the injury in the PLGA scaffold treatment group compared to the control (p<0.05, scaffold n=11, control n=11). This pilot study demonstrated that a PLGA scaffold improved regeneration of axons into peripheral nerve roots. However, the number of regenerating axons observed was limited and did not lead to functional recovery. Future experiments will employ a different scaffold material and possible growth factors or enzymes to increase axon populations.
    The spine journal: official journal of the North American Spine Society 02/2014; 14(9). DOI:10.1016/j.spinee.2014.01.059 · 2.80 Impact Factor
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    ABSTRACT: A novel biodegradable copolymer, poly(propylene fumarate-co-caprolactone) [P(PF-co-PL)], has been developed in our laboratory as an injectable scaffold for bone defect repair. In the current study, we evaluated the ability of P(PF-co-CL) to reconstitute the load bearing capacity of vertebral bodies with lytic lesions. Forty vertebral bodies from four fresh-frozen cadaveric thoracolumbar spines were used for this study. They were randomly divided into four groups: intact vertebral body (intact control), simulated defect without treatment (negative control), defect treated with P(PF-co-CL) (copolymer group), and defect treated with poly(methyl methacrylate) (PMMA group). Simulated metastatic lytic defects were made by removing a central core of the trabecular bone in each vertebral body with an approximate volume of 25% through an access hole in the side of the vertebrae. Defects were then filled by injecting either P(PF-co-CL) or PMMA in-situ crosslinkable formulations. After the spines were imaged with quantitative computerized tomography (QCT), single vertebral body segments were harvested for mechanical testing. Specimens were compressed until failure or to 25% reduction in body height and ultimate strength and elastic modulus of each specimen were then calculated from the force-displacement data. The average failure strength of the copolymer group was 1.83 times stronger than the untreated negative group and it closely matched the intact vertebral bodies (intact control). The PMMA treated vertebrae, however, had a failure strength 1.64 times larger than that of the intact controls. The elastic modulus followed the same trend. This modulus mismatch between PMMA-treated vertebrae and the host vertebrae could potentially induce a fracture cascade and degenerative changes in adjacent intervertebral discs. In contrast, P(PF-co-CL) restored the mechanical properties of the treated segments to be similar to the normal, intact, vertebrae. Therefore, P(PF-co-CL) may be a suitable alternative to PMMA for vertebroplasty treatment of vertebral bodies with lytic defects.
    Tissue Engineering Part A 11/2013; DOI:10.1089/ten.TEA.2013.0275 · 4.64 Impact Factor
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    ABSTRACT: Osteosarcoma is a bone tumor that affects children and young adults. 2-Methoxyestradiol (2-ME), a naturally occurring estrogen metabolite, kills osteosarcoma cells, but does not affect normal osteoblasts. In order to effectively target osteosarcoma and improve the therapeutic index of the drug 2-ME, we have encapsulated 2-ME in a composite of oligo-(polyethylene glycol) fumarate (OPF) hydrogel and poly (lactic-co-glycolic acid) (PLGA) microspheres and investigated the effect of polymer composition on 2-ME release kinetics and osteosarcoma cell survival. The in vitro study shows that 2-ME can be released in a controlled manner over 21-days. The initial burst releases observed on day 1 were 50% and 32% for OPF and OPF/PLGA composites, respectively. The extended release kinetics show that 100% of the encapsulated 2-ME is released by day 12 from OPF, whereas the OPF/PLGA composites showed a release of 85% on day 21. 2-ME released from the polymers was biologically active and blocked osteosarcoma cell proliferation in vitro. Also, comparison of 2-ME delivery in osteosarcoma cells in culture, shows that direct treatment has no effect after 3 days, whereas polymer-mediated delivery produces anti-tumor effects that could be sustained for 21 days. These findings show that the OPF and PLGA polymeric system may prove to be useful in controlled and sustained delivery of 2-ME and could be further explored in the treatment of osteosarcoma. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2013.
    Journal of Biomedical Materials Research Part A 09/2013; 101A(9). DOI:10.1002/jbm.a.34550 · 2.83 Impact Factor
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    ABSTRACT: Four biomaterial tubes, poly(lactic-co-glycolic acid) (PLGA), poly(caprolactone fumarate) (PCLF), a neutral oligo[(polyethylene glycol) fumarate] (OPF) hydrogel or a positively charged oligo[(polyethylene glycol) fumarate] (OPF(+)) hydrogel with a PCLF sleeve, have previously been shown to have benefits for nerve repair. However, no direct comparison to identify the optimal material have been made. Herein, these nerve tubes were implanted in a rat sciatic nerve model and nerve regeneration was quantified and compared by using accepted nerve assessment techniques. Using standard statistical methods, no significant differences of individual parameters were apparent between groups despite PCLF showing a tendency to perform better than the others. Using a mean-variance based ranking system of multiple independent parameters, statistical differences became apparent. It was clear that the PLCF tube supported significantly improved nerve regeneration and recovery compared to the other three biomaterial conduits. The ability to simultaneously compare a number of regenerative parameters and elucidate the best material from the combination of these individual parameters is of importance to the nerve regeneration area and has implications for the tissue engineering field. By using this method of comparison, a number of biomaterial constructs may be compared under similar conditions and the optimal construct elucidated using the minimal number of animals and materials.
    Biomaterials 08/2013; 34(34). DOI:10.1016/j.biomaterials.2013.07.086 · 8.31 Impact Factor
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    ABSTRACT: Osteosarcoma (OS) is a primary bone tumor that is most prevalent during adolescence. RUNX2, which stimulates differentiation and suppresses proliferation of osteoblasts, is deregulated in OS. Here, we define pathological roles of RUNX2 in the etiology of OS and mechanisms by which RUNX2 expression is stimulated. RUNX2 is often highly expressed in human OS biopsies and cell lines. Small interference RNA (siRNA)-mediated depletion of RUNX2 inhibits growth of U2OS OS cells. RUNX2 levels are inversely linked to loss of p53 (which predisposes to OS) in distinct OS cell lines and osteoblasts. RUNX2 protein levels decrease upon stabilization of p53 with the MDM2 inhibitor Nutlin-3. Elevated RUNX2 protein expression is post-transcriptionally regulated and directly linked to diminished expression of several validated RUNX2 targeting microRNAs (miRNAs) in human OS cells compared to mesenchymal progenitor cells. The p53-dependent miR-34c is the most significantly down-regulated RUNX2 targeting miRNA in OS. Exogenous supplementation of miR-34c markedly decreases RUNX2 protein levels, while 3UTR reporter assays establish RUNX2 as a direct target of miR-34c in OS cells. Importantly, Nutlin-3 mediated stabilization of p53 increases expression of miR-34c and decreases RUNX2. Thus, a novel RUNX2-p53-miR34 network controls cell growth of osseous cells and is compromised in OS.
    Journal of Biological Chemistry 05/2013; DOI:10.1074/jbc.M112.445890 · 4.60 Impact Factor
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    ABSTRACT: Osteosarcoma is the most common primary malignant bone tumor in children and young adults. Surgical resection and adjunctive chemotherapy are the only widely available options of treatment for this disease. Anti-tumor compound 2-Methoxyestradiol (2-ME) triggers cell death through the induction of apoptosis in osteosarcoma cells, but not in normal osteoblasts. In this report, we have investigated whether autophagy plays a role in 2-ME actions on osteosarcoma cells. Transmission electron microscopy imaging shows that 2-ME treatment leads to the accumulation of autophagosomes in human osteosarcoma cells. 2-ME induces the conversion of the microtubule-associated protein LC3-I to LC3-II, a biochemical marker of autophagy that is correlated with the formation of autophagosomes. Conversion to LC3-II is accompanied by protein degradation in 2-ME-treated cells. 2-ME does not induce autophagosome formation in normal primary human osteoblasts. In addition, 2-ME-dependent autophagosome formation in osteosarcoma cells requires ATG7 expression. Furthermore, 2-ME does not induce accumulation of autophagosomes in osteosarcoma cells that express dominant negative mutant RNA-dependent protein kinase (PKR) and are resistant to anti-proliferative and anti-tumor effects of 2-ME. Taken together, our study shows that 2-ME treatment induces PKR-dependent autophagy in osteosarcoma cells, and that autophagy could play an important role in 2-ME-mediated anti-tumor actions and in the control of osteosarcoma.
    PLoS ONE 03/2013; 8(3):e59406. DOI:10.1371/journal.pone.0059406 · 3.53 Impact Factor
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    Bone 03/2013; 53(1):320. DOI:10.1016/j.bone.2012.12.005 · 4.46 Impact Factor
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    ABSTRACT: Peripheral nerve reconstruction is seldom done in the acute phase of nerve injury due to concomitant injuries and the uncertainty of the extent of nerve damage. A proper model that mimics true clinical scenarios is critical but lacking. The aim of this study is to develop a standardized, delayed sciatic nerve repair model in rats and validate the feasibility of direct secondary neurrorraphy after various delay intervals. Immediately or 1, 4, 6, 8 and 12 weeks after sciatic nerve transection, nerve repair was carried out. A successful tension-free direct neurorraphy (TFDN) was defined when the gap was shorter than 4.0mm and the stumps could be reapproximated with 10-0 stitches without detachment. Compound muscle action potential (CMAP) was recorded postoperatively. Gaps between the two nerve stumps ranged from 0-9mm, the average being 1.36, 2.85, 3.43, 3.83 and 6.4mm in rats with 1, 4, 6, 8 and 12 week delay, respectively. The rate of successful TFDN was 78% overall. CMAP values of 1 and 4 week delay groups were not different from the immediate repair group, whereas CMAP amplitudes of 6, 8 and 12 week delay groups were significantly lower. A novel, standardized delayed nerve repair model is established. For this model to be sensitive, the interval between nerve injury and secondary repair should be at least over 4 weeks. Thereafter the longer the delay, the more challenging the model is for nerve regeneration. The choice of delay intervals can be tailored to meet specific requirements in future studies.
    Journal of neuroscience methods 01/2013; 214(1). DOI:10.1016/j.jneumeth.2013.01.003 · 1.96 Impact Factor
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    ABSTRACT: Treatment of large segmental bone defects remains an unsolved clinical challenge, despite a wide array of existing bone graft materials. This project was designed to rapidly assess and compare promising biodegradable osteoconductive scaffolds for use in the systematic development of new bone regeneration methodologies that combine scaffolds, sources of osteogenic cells, and bioactive scaffold modifications. Promising biomaterials and scaffold fabrication methods were identified in laboratories at Rutgers, MIT, Integra Life Sciences, and Mayo Clinic. Scaffolds were fabricated from various materials including: poly(L-lactide-co-glycolide) (PLGA), poly(L-lactide-co-ε-caprolactone) (PLCL), tyrosine-derived polycarbonate (TyrPC), and poly(propylene fumarate) (PPF). Highly porous three dimensional scaffolds were fabricated by three dimensional printing, laser stereolithography, or solvent casting followed by porogen leaching. The canine femoral multi-defect model (CFMD) was used to systematically compare scaffold performance and enable selection of the most promising substrate(s) on which to add cell sourcing options and bioactive surface modifications. Mineralized cancellous allograft (MCA) was used to provide a comparative reference to the current clinical standard for osteoconductive scaffolds. Percent bone volume within the defect was assessed four weeks after implantation using both micro-CT and limited histomorphometry. Bone formed at the periphery of all scaffolds with varying levels of radial ingrowth. MCA produced a rapid and advanced stage of bone formation and remodeling throughout the defect in 4 weeks, greatly exceeding the performance of all polymer scaffolds. Two scaffold constructs, TyrPCPL/TCP and PPF4SLA/HAPLGA Dip proved to be significantly better than alternative PLGA and PLCL scaffolds, justifying further development. Mineralized cancellous allograft remains the current standard for osteoconductive scaffolds.
    Tissue Engineering Part A 12/2012; 19(5-6). DOI:10.1089/ten.TEA.2012.0289 · 4.64 Impact Factor
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    ABSTRACT: Introduction: This project was designed to test the hypothesis that rapid intraoperative processing of bone marrow based on hyaluronan (HA) could be used to improve the outcome of local bone regeneration if the concentration and prevalence of marrow-derived connective tissue progenitors (CTPs) could be increased and nonprogenitors depleted before implantation. Methods: HA was used as a marker for positive selection of marrow-derived CTPs using magnetic separation (MS) to obtain a population of HA-positive cells with an increased CTP prevalence. Mineralized cancellous allograft (MCA) was used as an osteoconductive carrier scaffold for loading of HA-positive cells. The canine femoral multidefect model was used and four cylindrical defects measuring 10 mm in diameter and 15 mm in length were grafted with MCA combined with unprocessed marrow or with MS processed marrow that was enriched in HA(+) CTPs and depleted in red blood cells and nonprogenitors. Outcome was assessed at 4 weeks using quantitative 3D microcomputed tomography (micro-CT) analysis of bone formation and histomorphological assessment. Results: Histomorphological assessment showed a significant increase in new bone formation and in the vascular sinus area in the MS-processed defects. Robust bone formation was found throughout the defect area in both groups (defects grafted with unprocessed marrow or with MS processed marrow.) Percent bone volume in the defects, as assessed by micro-CT, was greater in defects engrafted with MS processed cells, but the difference was not statistically significant. Conclusion: Rapid intraoperative MS processing to enrich CTPs based on HA as a surface marker can be used to increase the concentration and prevalence of CTPs. MCA grafts supplemented with heparinized bone marrow or MS processed cells resulted in a robust and advanced stage of bone regeneration at 4 weeks. A greater new bone formation and vascular sinus area was found in defects grafted with MS processed cells. These data suggest that MS processing may be used to enhance the performance of marrow-derived CTPs in clinical bone regeneration procedures. Further assessment in a more stringent bone defect model is proposed.
    Tissue Engineering Part A 10/2012; 19(1-2). DOI:10.1089/ten.tea.2011.0622 · 4.64 Impact Factor
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    ABSTRACT: Histone deacetylase 3 (Hdac3) is a nuclear enzyme that removes acetyl groups from lysine residues in histones and other proteins to epigenetically regulate gene expression. Hdac3 interacts with bone-related transcription factors and co-factors such as Runx2 and Zfp521, and thus is poised to play a key role in the skeletal system. To understand the role of Hdac3 in osteoblasts and osteocytes, Hdac3 conditional knockout (CKO) mice were created with the Osteocalcin (OCN) promoter driving Cre expression. Hdac3 CKO(OCN) mice were of normal size and weight, but progressively lost trabecular and cortical bone mass with age. The Hdac3 CKO(OCN) mice exhibited reduced cortical bone mineralization and material properties and suffered frequent fractures. Bone resorption was lower, not higher, in the Hdac3 CKO(OCN) mice, suggesting that primary defects in osteoblasts caused the reduced bone mass. Indeed, reductions in bone formation were observed. Osteoblasts and osteocytes from Hdac3 CKO(OCN) mice showed increased DNA damage and reduced functional activity in vivo and in vitro. Thus, Hdac3 expression in osteoblasts and osteocytes is essential for bone maintenance during aging.
    Bone 10/2012; 52(1). DOI:10.1016/j.bone.2012.10.015 · 4.46 Impact Factor
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    ABSTRACT: Stimuli-responsive hydrogels have enormous potential in drug delivery applications. They can be used for site-specific drug delivery due to environmental variables in the body such as pH and temperature. In this study, we have developed pH-responsive microgels for the delivery of doxorubicin (DOX) in order to optimize its anti-tumor activity while minimizing its systemic toxicity. We used a copolymer of oligo(polyethylene glycol) fumarate (OPF) and sodium methacrylate (SMA) to fabricate the pH-responsive microgels. We demonstrated that the microgels were negatively charged, and the amounts of charge on the microgels were correlated with the SMA concentration in their formulation. The resulting microgels exhibited sensitivity to the pH and ionic strength of the surrounding environment. We demonstrated that DOX was efficiently loaded into the microgels and released in a controlled fashion via an ion-exchange mechanism. Our data revealed that the DOX release was influenced by the pH and ionic strength of the solution. Moreover, we designed a phenomenological mathematical model, based on a stretched exponential function, to quantitatively analyze the cumulative release of DOX. We found a linear correlation between the maximum release of DOX calculated from the model and the SMA concentration in the microgel formulation. The anti-tumor activity of the released DOX was assessed using a human chordoma cell line. Our data revealed that OPF-SMA microgels prolonged the cell killing effect of DOX.
    Acta biomaterialia 09/2012; 9(3). DOI:10.1016/j.actbio.2012.09.019 · 5.68 Impact Factor

Publication Stats

8k Citations
817.53 Total Impact Points

Institutions

  • 2002–2015
    • Mayo Foundation for Medical Education and Research
      • Department of Orthopaedic Surgery
      Рочестер, Michigan, United States
  • 1997–2014
    • Mayo Clinic - Rochester
      • • Division of Orthopaedic Surgery
      • • Department of Neurology
      • • Department of Orthopedics
      • • Department of Biomedical Engineering
      Rochester, Minnesota, United States
  • 2013
    • Tongji Hospital
      Wu-han-shih, Hubei, China
  • 2010
    • University of Michigan
      Ann Arbor, Michigan, United States
  • 2008–2010
    • University Medical Center Utrecht
      • Department of Orthopedics
      Utrecht, Provincie Utrecht, Netherlands
    • University of Virginia
      Charlottesville, Virginia, United States
  • 2009
    • University of Massachusetts Amherst
      Amherst Center, Massachusetts, United States
  • 2003–2008
    • University of California, San Diego
      • Department of Orthopaedic Surgery
      San Diego, CA, United States
  • 2007
    • Emory University
      Atlanta, Georgia, United States
  • 2004
    • Dartmouth–Hitchcock Medical Center
      Lebanon, New Hampshire, United States
  • 1999–2001
    • Rice University
      • Department of Bioengineering
      Houston, TX, United States
  • 1992–1997
    • Wilford Hall Ambulatory Surgery Center
      Lackland Air Force Base, Texas, United States
  • 1995
    • Massachusetts Institute of Technology
      • Department of Chemical Engineering
      Cambridge, Massachusetts, United States