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1.
Clin Orthop Relat Res ; 479(8): 1679-1687, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34252917

RESUMO

BACKGROUND: Narrative letters of recommendation are an important component of the residency application process. However, because narrative letters of recommendation are almost always positive, it is unclear whether those reviewing the letters understand the writer's intended strength of support for a given applicant. QUESTIONS/PURPOSES: (1) Is the perception of letter readers for narrative letters of recommendation consistent with the intention of the letter's author? (2) Is there inter-reviewer consistency in selection committee members' perceptions of the narrative letters of recommendation? METHODS: Letter writers who wrote two or more narrative letters of recommendation for applicants to one university-based orthopaedic residency program for the 2014 to 2015 application cycle were sent a survey linked to a specific letter of recommendation they authored to assess the intended meaning regarding the strength of an applicant. A total of 247 unstructured letters of recommendation and accompanying surveys were sent to their authors, and 157 surveys were returned and form the basis of this study (response percentage 64%). The seven core members of the admissions committee (of 22 total reviewers) at a university-based residency program were sent a similar survey regarding their perception of the letter. To answer our research question about whether letter readers' perceptions about a candidate were consistent with the letter writer's intention, we used kappa values to determine agreement for survey questions involving discrete variables and Spearman correlation coefficients (SCCs) to determine agreement for survey questions involving continuous variables. To answer our research question regarding inter-reviewer consistency among the seven faculty members, we compared the letter readers' responses to each survey question using intraclass correlation coefficients (ICCs). RESULTS: There was a negligible to moderate correlation between the intended and perceived strength of the letters (SCC 0.26 to 0.57), with only one of seven letter readers scoring in the moderate correlation category. When stratifying the applicants into thirds, there was only slight agreement (kappa 0.07 to 0.19) between the writers and reviewers. There were similarly low kappa values for agreement about how the writers and readers felt regarding the candidate matching into their program (kappa 0.14 to 0.30). The ICC for each question among the seven faculty reviewers ranged from poor to moderate (ICC 0.42 to 0.52). CONCLUSION: Our results demonstrate that the reader's perception of narrative letters of recommendation did not correlate well with the letter writer's intended meaning and was not consistent between letter readers at a single university-based urban orthopaedic surgery residency program. CLINICAL RELEVANCE: Given the low correlation between the intended strength of the letter writers and the perceived strength of those letters, we believe that other options such as a slider bar or agreed-upon wording as is used in many dean's letters may be helpful.


Assuntos
Correspondência como Assunto , Docentes de Medicina/psicologia , Internato e Residência/organização & administração , Ortopedia/educação , Seleção de Pessoal/métodos , Adulto , Avaliação Educacional , Feminino , Humanos , Intenção , Masculino , Pessoa de Meia-Idade , Narração , Estatísticas não Paramétricas , Estudantes de Medicina , Inquéritos e Questionários
2.
Arthrosc Sports Med Rehabil ; 3(6): e1899-e1904, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34977646

RESUMO

PURPOSE: Evidenced-based decision-making is rooted in comparative clinical studies; however, a small number of outcome event reversals have the potential to change study significance. The purpose of this study was to determine the utility of applying fragility analysis to comparative studies in the published orthopaedic shoulder literature. METHODS: Comparative clinical shoulder research studies reporting 1:1 dichotomous categorical data were analyzed in 6 leading orthopaedic journals between 2006 and 2016. Statistical significance was defined as a P value of less than .05. The fragility index (FI) for each study outcome was determined by the number of event reversals required to change the P value to either greater or less than 0.05, thus changing the study conclusions. The associated fragility quotient (FQ) was determined by dividing the FI by the total population comprising a particular outcome. RESULTS: Of the 23,897 studies screened, 3,591 met search criteria, with 198 comparative studies ultimately included for analysis, 67 of which were randomized controlled trials. There were 357 total outcome events with 74 reported as significant and 283 as not significant. The FI was 4 (IQR 2-6) with an associated FQ of 0.066 (interquartile range [IQR] 0.038-0.102). There was no difference in statistical fragility between randomized and nonrandomized trials with both revealing a FI of 4 and FQ of 0.068 (IQR 0.044-0.107) and 0.065 (IQR 0.031-0.101), respectively. CONCLUSIONS: This current analysis reveals that comparative shoulder studies published in six leading orthopaedic journals are at risk of statistical fragility. As such, contemporary clinical shoulder literature may not be as robust as traditionally perceived with the reversal of only a few outcome events required to change study significance. Therefore, we advocate the reporting of both FI and FQ in addition to the P value as statistical complements to all comparative investigations to provide a more comprehensive understanding of trial stability and significance in the published shoulder literature. CLINICAL RELEVANCE: Comparative study designs are commonly employed in shoulder research. Several studies in both the general medical and orthopaedic literature have identified a lack of statistical robustness through comprehensive fragility analysis. Our findings demonstrate the P value may be an inadequate independent statistical metric requiring the complement of a FI and FQ to aid in the interpretation and understanding of study significance for clinical decision-making.

3.
JBJS Case Connect ; 10(2): e0054, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32649085

RESUMO

CASE: A 46-year-old man presented with extensive swelling and ecchymosis of the arm and antecubital fossa after a 4-foot fall from a ladder in which he attempted to arrest his decent by grabbing onto a wooden ceiling beam. Ultrasound and magnetic resonance imaging confirmed a complete intrasubstance rupture of the biceps brachii. Nonoperative management was recommended and, at 9-week follow-up, the patient had resumed light weightlifting and demonstrated painless full active range of motion. CONCLUSIONS: Uncommon complete intrasubstance biceps brachii ruptures can occur via an atypical mechanism of isotonic eccentric muscle contraction and satisfactory results may be realized through nonoperative management.


Assuntos
Traumatismos do Braço/diagnóstico por imagem , Músculo Esquelético/lesões , Ruptura/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Ultrassonografia
4.
J Orthop Trauma ; 34(2): 108-112, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31809416

RESUMO

OBJECTIVE: To compare the volar Henry and dorsal Thompson approaches with respect to outcomes and complications for proximal third radial shaft fractures. DESIGN: Multicenter retrospective cohort study. PATIENTS/PARTICIPANTS: Patients with proximal third radial shaft fractures ± associated ulna fractures (OTA/AO 2R1 ± 2U1) treated operatively at 11 trauma centers were included. INTERVENTION: Patient demographics and injury, fracture, and surgical data were recorded. Final range of motion and complications of infection, neurologic injury, compartment syndrome, and malunion/nonunion were compared for volar versus dorsal approaches. MAIN OUTCOME: The main outcome was difference in complications between patients treated with volar versus dorsal approach. RESULTS: At an average follow-up of 292 days, 202 patients (range, 18-84 years) with proximal third radial shaft fractures were followed through union or nonunion. One hundred fifty-five patients were fixed via volar and 47 via dorsal approach. Patients treated via dorsal approach had fractures that were on average 16 mm more proximal than those approached volarly, which did not translate to more screw fixation proximal to the fracture. Complications occurred in 11% of volar and 21% of dorsal approaches with no statistical difference. CONCLUSIONS: There was no statistical difference in complication rates between volar and dorsal approaches. Specifically, fixation to the level of the tuberosity is safely accomplished via the volar approach. This series demonstrates the safety of the volar Henry approach for proximal third radial shaft fractures. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.


Assuntos
Placas Ósseas , Fraturas do Rádio , Fixação Interna de Fraturas , Humanos , Rádio (Anatomia) , Fraturas do Rádio/cirurgia , Amplitude de Movimento Articular , Estudos Retrospectivos
5.
J Hand Surg Am ; 44(12): 1101.e1-1101.e5, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31585748

RESUMO

Hook of the hamate fractures can be treated by various methods including cast immobilization, open reduction, and internal fixation and excision. Usually, those individuals who elect for excision have acute fractures and need to return to sporting activity or work quickly or have nonunions with persistent symptoms. There is a paucity of descriptions in the literature and textbooks of a technique to safely excise the hook of the hamate. The authors present a method of safely exposing and removing the hook of the hamate by visualizing the potential structures at risk: the motor branch of the ulnar nerve, the ulnar digital nerve to the little finger, and the flexor tendons to the ring and little fingers by an approach through Guyon's canal and the proximal ulnar border of the carpal tunnel.


Assuntos
Fixação Interna de Fraturas/métodos , Fraturas Ósseas/cirurgia , Hamato/lesões , Fraturas Ósseas/diagnóstico por imagem , Hamato/diagnóstico por imagem , Humanos
6.
J Orthop Trauma ; 33(12): e466-e470, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31356443

RESUMO

OBJECTIVES: To evaluate the stability of statistical findings in the fracture care literature based on minor changes in event rates and to determine the utility of applying both the Fragility Index (FI) and Fragility Quotient (FQ) to comparative orthopaedic trauma trials. METHODS: All fracture care studies from 1991 to 2013 in the Journal of Bone and Joint Surgery and the Journal of Orthopaedic Trauma were screened. The FI was determined by altering the number of reported outcome events, a single event at time, until a reversal of statistical significance was determined. The associated FQ was determined by dividing the FI by the total sample size. RESULTS: Of the 4040 studies evaluated, 198 comparative studies met inclusion criteria with a reported 253 primary and 522 secondary outcome events. There were 118 randomized controlled trials and 80 retrospective comparative studies. Of the 775 total outcome events, 235 were initially reported as significant. The median FI for the entire study was only 5 with an associated FQ of 0.046. This represents just 3.8% of the total study population. CONCLUSIONS: The robustness of comparative trials in the orthopaedic trauma literature may not be as stable as previously thought with only a few event reversals required to alter trial significance. We therefore recommend triple reporting of a P value, FI, and FQ to aid in the evaluation and interpretation of statistical stability and quantitative significance in comparative orthopaedic trauma trials.


Assuntos
Pesquisa Biomédica/organização & administração , Interpretação Estatística de Dados , Fraturas Ósseas/complicações , Fraturas Ósseas/cirurgia , Fragilidade/complicações , Ensaios Clínicos como Assunto , Estudos de Coortes , Humanos , Reprodutibilidade dos Testes
7.
J Orthop Trauma ; 33(6): 269-275, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31124908

RESUMO

OBJECTIVE: Explore the validity of the Caprini Score in orthopaedic patients with lower-extremity fractures. DESIGN: Retrospective cohort study. SETTING: Level I trauma academic medical center. PATIENTS/PARTICIPANTS: Eight hundred forty-eight patients with lower-extremity fractures from 2002 to 2015 with exclusion criteria: minors, follow-up less than 30 days. INTERVENTION: Stratify patients into 2 groups: high-risk (pelvic and acetabular fractures) and low-risk groups (isolated foot and ankle fractures). MAIN OUTCOME: Caprini Score, fracture classification, length of follow-up, deep vein thrombosis (DVT) chemoprophylaxis, and venothromboembolism (VTE) events [DVT and/or pulmonary embolism (PE)] diagnosed with objective testing. RESULTS: Eight hundred forty-eight patients (499 M; 349 F) 18-93 years of age (average 43.7) with average body mass index of 29. Three hundred high-risk and 548 low-risk patients with no differences in demographics with average follow-up of 288 days. There were 33 (3.9%) VTE events, which were more common in the high-risk group (8%: 9 DVT, 15 PE) than the low-risk group (1.6%: 8 DVT, 1 PE) (P < 0.0001). The cutoff that best-predicted VTE events based on receiver-operating curves was 12 (c = 0.74) in the high-risk group, 11 (c = 0.79) in the low-risk group, and 12 (c = 0.83) overall. CONCLUSION: There was a significant lower VTE rate found in the low-risk group, but the Caprini prediction model was not significantly different between the 2 groups. This displays that patient factors play a large role in the development of VTE events independent of injury type. The Caprini score may help identify patients who may require increased protection. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.


Assuntos
Fraturas Ósseas/cirurgia , Complicações Pós-Operatórias/epidemiologia , Tromboembolia Venosa/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Procedimentos Ortopédicos , Reprodutibilidade dos Testes , Estudos Retrospectivos , Medição de Risco , Adulto Jovem
8.
J Am Acad Orthop Surg ; 27(7): e324-e329, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30325880

RESUMO

INTRODUCTION: Comparative trials evaluating categorical outcomes have important implications on surgical decision making. The purpose of this study was to examine the statistical stability of sports medicine research. METHODS: Comparative clinical sports medicine research studies involving anterior cruciate ligament, meniscus, and knee instability were reviewed in two journals between 2006 and 2016. The statistical stability for each study outcome was determined by the number of event reversals required to change the P value to either greater or less than 0.05. The number of patients lost to follow-up was also determined. RESULTS: Of the 1,505 studies screened, 102 studies were included for analysis, 40 of which were randomized controlled trials. There were 339 total outcome events, with 98 significant and 241 not significant. The Fragility Index, or the median number of events required to change the statistical significance of the overall study, was five (interquartile range, 3 to 8) or 5.4% of the total study population. In addition, the average number of patients lost to follow-up was 7.9, which is greater than the number needed to change the significance of each study arm and the entire study population. CONCLUSION: Results in the comparative sports medicine literature may not be as stable as previously thought, with only a small percentage of outcome events needed to change study significance. Outcomes research based on a single discreet P value cutoff may be misleading.


Assuntos
Tomada de Decisão Clínica , Avaliação de Resultados em Cuidados de Saúde , Pesquisa/estatística & dados numéricos , Medicina Esportiva , Ligamento Cruzado Anterior , Seguimentos , Humanos , Instabilidade Articular , Articulação do Joelho , Menisco , Ensaios Clínicos Controlados Aleatórios como Assunto
9.
J Hand Surg Am ; 43(6): 516-522.e1, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29544978

RESUMO

PURPOSE: We investigated whether written guidelines for surgeons and educational handouts for patients regarding safe and effective opioid use after hand surgery could reduce prescription sizes while achieving high patient satisfaction and a low refill rate. METHODS: All patients undergoing isolated carpal tunnel release or distal radius volar locked plating in a hand surgery group practice during a 6-month period were prospectively enrolled. Surgeons prescribed analgesics at their own discretion based on written guidelines. Patients received an educational handout regarding safe opioid use and disposal, a diary to record daily pain visual analog scale score and consumption of opioid and over-the-counter (OTC) analgesics, and a pain catastrophizing scale questionnaire. Collected data were compared with a retrospective cohort of the same surgeons, procedures, and period 1 year earlier. RESULTS: In the carpal tunnel release group (121 patients), average prescription size was 10 opioid pills, compared with 22 in the prior year. Average consumption was 3 opioid pills, supplemented with 11 OTC pills. In the volar locked plating group (24 patients), average prescription size was 25 opioid pills, compared with 39 in the prior year. Average consumption was 16 opioid pills, supplemented with 20 OTC pills. Patient satisfaction was comparably high in both groups. Eight patients required opioid refills overall. Patients with pain catastrophizing scale greater than 10 used more than twice as many opioid pills. Of 109 patients with leftover opioids, 10 reported proper disposal. CONCLUSIONS: Written guidelines and educational handouts significantly reduced the number of prescribed opioid pills by 35% to 55% while achieving high patient satisfaction and a low refill rate. We recommend 5 to 10 opioid pills for carpal tunnel release and 20 to 30 for distal radius volar plating. Pain catastrophizing is associated with greater opioid consumption and may help target patients for additional support. Potential for opioid abuse and diversion may persist despite these interventions. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic II.


Assuntos
Analgésicos Opioides/uso terapêutico , Protocolos Clínicos , Transtornos Relacionados ao Uso de Opioides/prevenção & controle , Dor Pós-Operatória/tratamento farmacológico , Uso Indevido de Medicamentos sob Prescrição/prevenção & controle , Adulto , Idoso , Idoso de 80 Anos ou mais , Analgésicos não Narcóticos/uso terapêutico , Placas Ósseas , Síndrome do Túnel Carpal/cirurgia , Descompressão Cirúrgica , Prescrições de Medicamentos/estatística & dados numéricos , Uso de Medicamentos , Feminino , Fixação Interna de Fraturas , Humanos , Masculino , Massachusetts , Pessoa de Meia-Idade , Educação de Pacientes como Assunto , Satisfação do Paciente , Estudos Prospectivos , Fraturas do Rádio/cirurgia , Inquéritos e Questionários
10.
Phys Sportsmed ; 46(1): 24-29, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29202636

RESUMO

BACKGROUND: Ankle sprain is one of the most common musculoskeletal injuries among young athletes, and there remains a gap in the literature regarding susceptibility to such injuries among physically active youth. OBJECTIVE: The primary purpose of this study was to determine the associations between sex, a history of ankle sprain, and ankle range of motion (ROM) in pediatric and adolescent athletes. METHODS: Athletes under the age of 18 years old who presented to a sports injury prevention center underwent ankle ROM measurements including plantarflexion (PF), inversion (IV), and eversion (EV). A two-way analysis of covariance (ANCOVA) was performed to examine effect of sex and a history of ankle sprain on ROMs. Also, a binary logistic regression was performed to investigate variables that are associated with a history of ankle injury. RESULTS: Among 452 pediatric and adolescent athletes [268 females (13.6 ± 2.3 years old) and 184 males (13.3 ± 2.5 years old)], 128 reported a history of previous ankle sprain. Females demonstrated significantly increased ROMs (PF and IV bilaterally, and right EV) compared to males while there was no effect of a history of ankle sprain on ROMs. Female sex was independently associated with a history of ankle sprain. CONCLUSION: There was a strong effect of female sex on ROMs rather than a history of ankle injury history. Additionally, pediatric and adolescent females have greater odds of a history of ankle sprain when compared to their male counterparts.


Assuntos
Traumatismos do Tornozelo/complicações , Articulação do Tornozelo , Traumatismos em Atletas/complicações , Amplitude de Movimento Articular , Esportes , Entorses e Distensões/complicações , Adolescente , Análise de Variância , Atletas , Criança , Feminino , Humanos , Masculino , Anamnese , Fatores Sexuais , Adulto Jovem
11.
World J Orthop ; 7(6): 392-400, 2016 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-27335815

RESUMO

AIM: To evaluate whether anterior cruciate ligament (ACL) allograft irradiation is effective for sterility without compromising graft integrity and increasing failure rate. METHODS: A literature search was conducted using PubMed, Cochrane, and Google. The following search terms were used: "Gamma irradiation AND anterior cruciate ligament AND allograft" with a return of 30 items. Filters used included: English language, years 1990-2015. There were 6 hits that were not reviewed, as there were only abstracts available. Another 5 hits were discarded, as they did not pertain to the topic of interest. There were 9 more articles that were excluded: Three studies were performed on animals and 6 studies were meta-analyses. Therefore, a total of 10 articles were applicable to review. RESULTS: There is a delicate dosing crossover where gamma irradiation is both effective for sterility without catastrophically compromising the structural integrity of the graft. Of note, low dose irradiation is considered less than 2.0 Mrad, moderate dose is between 2.1-2.4 Mrad, and high dose is greater than or equal to 2.5 Mrad. Based upon the results of the literature search, the optimal threshold for sterilization was found to be sterilization at less than 2.2 Mrad of gamma irradiation with the important caveat of being performed at low temperatures. The graft selection process also must include thorough donor screening and testing as well as harvesting the tissue in a sterile fashion. Utilization of higher dose (≥ 2.5 Mrad) of irradiation causes greater allograft tissue laxity that results in greater graft failure rate clinically in patients after ACL reconstruction. CONCLUSION: Allograft ACL graft gamma irradiated with less than 2.2 Mrad appears to be a reasonable alternative to autograft for patients above 25 years of age.

12.
J Pediatr Orthop ; 35(7): 651-6, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25393567

RESUMO

BACKGROUND: Displaced tibial spine fractures are frequently treated with surgical reduction and fixation, but no comparison studies have been performed. This study was undertaken to compare fragment reduction and adverse outcomes between open arthrotomy [open reduction and internal fixation (ORIF)], arthroscopy [arthroscopic-assisted internal fixation (AAIF)], and closed management [closed management and casting (CMC)] of pediatric tibial spine fractures. METHODS: A retrospective review of children treated for displaced tibial spine fractures from 2003 to 2011 was performed after categorizing into the 3 treatment groups. Demographics, mechanism of injury, radiographic measures (plain film and computed tomography), treatment, duration of immobilization and follow-up, final range of motion, and complications were recorded. Families were contacted to obtain long-term Lysholm scores, return to activity, pain, and satisfaction with treatment. RESULTS: Seventy-six children (mean age, 12.4 y) met criteria with 29 ORIF, 28 AAIF, and 19 CMC. Radiographic measurements between x-ray and computed tomography scans found a mean error of 1 mm (SD=1.33 mm; inter-class coefficient = 0.977, P < 0.001). Initial fracture displacement was similar between AAIF and ORIF, 10.3 ± 4.4 mm and 10.8 ± 3.9 mm; but, less in CMC group (5.3 ± 2.6 mm). The mean reduction amount was 8.6 ± 4.7, 9.1 ± 4.0, and 2.3 ± 2.6 mm, respectively. A Bonferroni post hoc analysis revealed a difference between surgical and nonoperative reduction (P < 0.001), but not between AAIF and ORIF (P=0.9). Arthrofibrosis occurred with equal frequency in surgical cohorts (AAIF 12.5%, ORIF 11.1%), compared with none in the CMC group. Yet, the CMC group had a 16.7% risk for reoperation secondary to instability, loose bodies, or impingement. Twenty-four percent of each cohort was available (at mean 6.0 y) for interview with mean (median) Lysholm score: ORIF 97.4 (99), AAIF 95 (100), and CMC 86 (97.5), P = 0.35. CONCLUSIONS: Open or arthroscopic treatment of displaced tibial spine fractures affords a better reduction than closed management, but with higher risk for arthrofibrosis. Closed management may be successful when displacement is < 5 mm, and advanced imaging may not be necessary to delineate the amount of displacement.


Assuntos
Fixação Interna de Fraturas/métodos , Fraturas da Tíbia/cirurgia , Adolescente , Análise de Variância , Artroscopia/métodos , Criança , Pré-Escolar , Gerenciamento Clínico , Feminino , Humanos , Luxações Articulares/cirurgia , Masculino , Amplitude de Movimento Articular , Reoperação/estatística & dados numéricos , Estudos Retrospectivos , Fraturas da Tíbia/diagnóstico por imagem , Tomografia Computadorizada por Raios X
13.
Orthop Clin North Am ; 44(4): 541-51, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24095070

RESUMO

This article evaluates the spectrum of epidemiology and treatment of children presenting with shoulder pain. These injuries are discussed to further understand the mechanism of injury, the variation of these injuries with age, treatment options, and outcomes and complications that may arise. A retrospective clinical review was performed to compliment the findings of the literature review.


Assuntos
Traumatismos em Atletas/cirurgia , Fraturas Ósseas/cirurgia , Lesões do Ombro , Adolescente , Fatores Etários , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Osteogênese , Ombro/inervação , Ombro/fisiopatologia
14.
Mol Pharm ; 5(5): 876-84, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18710254

RESUMO

Acid-degradable particles containing a model protein antigen, ovalbumin, were prepared from a polyurethane with acetal moieties embedded throughout the polymer, and characterized by dynamic light scattering and transmission electron microscopy. The small molecule degradation byproduct of the particles was synthesized and tested in vitro for toxicity indicating an LC 50 of 12,500 microg/mL. A new liquid chromatography-mass spectrometry technique was developed to monitor the in vitro degradation of these particles. The degradation byproduct inside RAW macrophages was at its highest level after 24 h of culture and was efficiently exocytosed until it was no longer detectable after 4 days. When tested in vitro, these particles induced a substantial increase in the presentation of the immunodominant ovalbumin-derived peptide SIINFEKL in both macrophages and dendritic cells. In addition, vaccination with these particles generated a cytotoxic T-lymphocyte response that was superior to both free ovalbumin and particles made from an analogous but slower-degrading acid-labile polyurethane polymer. Overall, we present a fully degradable polymer system with nontoxic byproducts, which may find use in various biomedical applications including protein-based vaccines.


Assuntos
Portadores de Fármacos/administração & dosagem , Nanopartículas/administração & dosagem , Poliuretanos/metabolismo , Proteínas/química , Vacinas/administração & dosagem , Ácidos/metabolismo , Animais , Apresentação de Antígeno/imunologia , Células Cultivadas , Portadores de Fármacos/química , Portadores de Fármacos/metabolismo , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Epitopos Imunodominantes/imunologia , Luz , Macrófagos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Eletrônica de Transmissão , Estrutura Molecular , Nanopartículas/química , Ovalbumina/química , Ovalbumina/imunologia , Tamanho da Partícula , Poliuretanos/química , Poliuretanos/farmacocinética , Proteínas/imunologia , Espalhamento de Radiação , Linfócitos T Citotóxicos/imunologia , Vacinas/química , Vacinas/imunologia
15.
J Am Chem Soc ; 130(32): 10494-5, 2008 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-18630909

RESUMO

Dextran, a biocompatible, water-soluble polysaccharide, was modified at its hydroxyls with acetal moieties such that it became insoluble in water but freely soluble in common organic solvents enabling its use in the facile preparation of acid-sensitive microparticles. These particles degrade in a pH-dependent manner: FITC-dextran was released with a half-life at 37 degrees C of 10 h at pH 5.0 compared to a half-life of approximately 15 days at pH 7.4. Both hydrophobic and hydrophilic cargoes were successfully loaded into these particles using single and double emulsion techniques, respectively. When used in a model vaccine application, particles loaded with the protein ovalbumin (OVA) increased the presentation of OVA-derived peptides to CD8+ T-cells 16-fold relative to OVA alone. Additionally, this dextran derivative was found to be nontoxic in preliminary in vitro cytotoxicity assays. Owing to its ease of preparation, processability, pH-sensitivity, and biocompatibility, this type of modified dextran should find use in numerous drug delivery applications.


Assuntos
Materiais Biocompatíveis/síntese química , Dextranos/síntese química , Acetais/química , Ácidos/química , Animais , Apresentação de Antígeno , Materiais Biocompatíveis/química , Materiais Biocompatíveis/uso terapêutico , Materiais Biocompatíveis/toxicidade , Biodegradação Ambiental , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linhagem Celular , Dextranos/química , Dextranos/uso terapêutico , Dextranos/toxicidade , Sistemas de Liberação de Medicamentos , Fluoresceína-5-Isotiocianato/análogos & derivados , Fluoresceína-5-Isotiocianato/química , Concentração de Íons de Hidrogênio , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Teste de Materiais , Camundongos , Ovalbumina/imunologia , Vacinas/química , Vacinas/imunologia
16.
Bioconjug Chem ; 19(4): 911-9, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18373356

RESUMO

A library of polyurethanes and polyureas with different hydrophobicities containing the same acid-degradable dimethyl ketal moiety embedded in the polymer main chain have been prepared. All polymers were synthesized using an AA-BB type step-growth polymerization by reaction of bis(p-nitrophenyl carbamate/carbonate) or diisocyanate monomers with an acid-degradable, ketal-containing diamine. These polymers were designed to hydrolyze at different rates in mildly acidic conditions as a function of their hydrophobicity to afford small molecules only with no polymeric byproduct. The library of polymers was screened for the formation of microparticles using a double emulsion technique. The microparticles that were obtained degraded significantly faster at acidic pH (5.0) than at physiological pH (7.4) with degradation kinetics related to the hydrophobicity of the starting polymer. In vitro studies demonstrated the ability of the FITC-BSA loaded microparticles to be phagocytosed by macrophages resulting in a 10-fold increase in the protein uptake compared to a free protein control; in addition, the microparticles were found to be nontoxic at the concentrations tested of up to 1 mg/mL. The ease of preparation of the polymers coupled with the ability to tune their hydrophobicity and the high acid sensitivity of the microparticles identify this new class of materials as promising candidates for the delivery of bioactive materials.


Assuntos
Acetais/química , Ácidos/química , Materiais Biocompatíveis/química , Portadores de Fármacos/química , Microesferas , Polímeros/química , Acetais/síntese química , Acetais/metabolismo , Acetais/toxicidade , Materiais Biocompatíveis/síntese química , Materiais Biocompatíveis/metabolismo , Materiais Biocompatíveis/toxicidade , Portadores de Fármacos/síntese química , Portadores de Fármacos/metabolismo , Portadores de Fármacos/toxicidade , Concentração de Íons de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Cinética , Macrófagos/citologia , Macrófagos/metabolismo , Fagocitose , Polímeros/síntese química , Polímeros/metabolismo , Polímeros/toxicidade , Fatores de Tempo , Água/química
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