Publications by authors named "Roy K Aaron"

39 Publications

Bounding the Implications of Noncompliance in Randomized Controlled Trials in Orthopaedics: An Example in Arthroscopic Surgery.

J Am Acad Orthop Surg 2021 Jun 14. Epub 2021 Jun 14.

From the Department of Health Services, Policy & Practice, Brown University School of Public Health (Forbes, Trikalinos), the Center for Evidence Synthesis in Health (CESH), Brown University School of Public Health (Forbes, Trikalinos), and the Department of Orthopedics, Warren Alpert Medical School of Brown University, Providence, RI (Aaron).

Introduction: Randomized controlled trials (RCTs) are not impervious to bias especially when there are substantial numbers of patients who cross over from the treatment assigned by randomization to another treatment group, leading to loss of confidence in study results. The goals of this study were to (1) quantify the effects of crossovers on RCTs, (2) describe the specific effects of crossovers on RCTs for arthroscopic meniscectomy for osteoarthritis of the knee (APM/OAK), and (3) assess the confidence in APM/OAK in which there have been substantial numbers of patients crossing over to another treatment group than that assigned.

Methods: Studies were included that were RCTs of APM/OAK with intention-to-treat (ITT) analysis and illustrated the problem of crossovers on confidence in the analysis. Studies were excluded if they consisted of APM for conditions other than OAK or had unavailability of data needed for the analysis. For eligible RCTs, the ITT effect was calculated; bounds for the average treatment effect (ATE) and the complier ATE were assessed by estimating confidence intervals for the bound through robust Bayesian analysis.

Results: The eligible studies had different comparators and, therefore, were analyzed individually. Data were not pooled. The most extreme point estimates (with 95% confidence interval) for ITT ranged from -0.01 to 0.04 (-0.16 to 0.16); for ATE with no assumptions, 0.38 (-0.58 to 0.43) to 0.62 (0.56 to 0.70); for ATE with minimum assumptions, -0.50 (-0.22 to 0.10) to 0.61 (0.53 to 0.57); and for complier ATE, -0.01 to 0.07 (-0.22 to 0.24).

Discussion: These data suggest large bounds, crossing the threshold of "no effect," which indicates a high degree of uncertainty and low confidence in the RCTs studied. The results demonstrate that when there are crossovers, ITT analyses do not estimate the ATE and confidence in the results of these RCTs is low.

Data Availability: All analyzed data are provided in the article.

Level Of Evidence: Level I (therapeutic study = RCT).
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http://dx.doi.org/10.5435/JAAOS-D-20-00919DOI Listing
June 2021

Pulsed Electromagnetic Field Stimulation of Bone Healing and Joint Preservation: Cellular Mechanisms of Skeletal Response.

J Am Acad Orthop Surg Glob Res Rev 2020 05;4(5):e1900155

From the IGEA, Clinical Biophysics, Carpi, Italy (Dr. Cadossi), the Department of Biomedical and Specialty Surgical Sciences, Azienda Ospedaliero-Universitaria di Ferrara, Arcispedale Sant'Anna, University of Ferrara, Ferrara, Italy (Dr. Massari), and the Department of Orthopaedics, Warren Alpert Medical School, Brown University, Providence, RI (Ms. Racine-Avila and Dr. Aaron).

The US FDA has approved pulsed electromagnetic fields (PEMFs) as a safe and effective treatment for nonunions of bone. Despite its clinical use, the mechanisms of action of electromagnetic stimulation of the skeleton have been elusive. Recently, cell membrane receptors have been identified as the site of action of PEMF and provide a mechanistic rationale for clinical use. This review highlights key processes in cell responses to PEMF as follows: (1) signal transduction through A2A and A3 adenosine cell membrane receptors and (2) dose-response effects on the synthesis of structural and signaling extracellular matrix (ECM) components. Through these actions, PEMF can increase the structural integrity of bone and cartilage ECM, enhancing repair, and alter the homeostatic balance of signaling cytokines, producing anti-inflammatory effects. PEMFs exert a proanabolic effect on the bone and cartilage matrix and a chondroprotective effect counteracting the catabolic effects of inflammation in the joint environment. Understanding of PEMF membrane targets, and of the specific intracellular pathways involved, culminating in the synthesis of ECM proteins and reduction in inflammatory cytokines, should enhance confidence in the clinical use of PEMF and the identification of clinical conditions likely to be affected by PEMF exposure.
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http://dx.doi.org/10.5435/JAAOSGlobal-D-19-00155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7434032PMC
May 2020

Pulsed electromagnetic fields promote repair of focal articular cartilage defects with engineered osteochondral constructs.

Biotechnol Bioeng 2020 05 5;117(5):1584-1596. Epub 2020 Feb 5.

Department of Biomedical Engineering, Columbia University, New York, NY.

Articular cartilage injuries are a common source of joint pain and dysfunction. We hypothesized that pulsed electromagnetic fields (PEMFs) would improve growth and healing of tissue-engineered cartilage grafts in a direction-dependent manner. PEMF stimulation of engineered cartilage constructs was first evaluated in vitro using passaged adult canine chondrocytes embedded in an agarose hydrogel scaffold. PEMF coils oriented parallel to the articular surface induced superior repair stiffness compared to both perpendicular PEMF (p = .026) and control (p = .012). This was correlated with increased glycosaminoglycan deposition in both parallel and perpendicular PEMF orientations compared to control (p = .010 and .028, respectively). Following in vitro optimization, the potential clinical translation of PEMF was evaluated in a preliminary in vivo preclinical adult canine model. Engineered osteochondral constructs (∅ 6 mm × 6 mm thick, devitalized bone base) were cultured to maturity and implanted into focal defects created in the stifle (knee) joint. To assess expedited early repair, animals were assessed after a 3-month recovery period, with microfracture repairs serving as an additional clinical control. In vivo, PEMF led to a greater likelihood of normal chondrocyte (odds ratio [OR]: 2.5, p = .051) and proteoglycan (OR: 5.0, p = .013) histological scores in engineered constructs. Interestingly, engineered constructs outperformed microfracture in clinical scoring, regardless of PEMF treatment (p < .05). Overall, the studies provided evidence that PEMF stimulation enhanced engineered cartilage growth and repair, demonstrating a potential low-cost, low-risk, noninvasive treatment modality for expediting early cartilage repair.
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http://dx.doi.org/10.1002/bit.27287DOI Listing
May 2020

Contribution of Circulatory Disturbances in Subchondral Bone to the Pathophysiology of Osteoarthritis.

Curr Rheumatol Rep 2017 Aug;19(8):49

Department of Radiology, Weill Cornell Medicine Citigroup Biomedical Imaging Center , 516 E 72nd Street, New York, NY, 10021, USA.

Purpose Of Review: This review describes the contributions of abnormal bone circulation to the pathophysiology of osteoarthritis. Combining dynamic imaging with MRI and PET with previous observations reveals that venous stasis and a venous outlet syndrome is most likely the key circulatory pathology associated with the initiation or progression of osteoarthritis.

Recent Findings: MRI and PET have revealed that venous outflow obstruction results in physicochemical changes in subchondral bone to which osteoblasts are responsive. The osteoblasts express an altered pattern of cytokines, many of which can serve as structural or signaling molecules contributing to both bone remodeling and cartilage degeneration. The patterns of circulatory changes are associated with alterations in the physicochemical environment of subchondral bone, including hypoxia. Osteoblast cytokines can transit the subchondral bone plate and calcified cartilage and communicate with chondrocytes.
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http://dx.doi.org/10.1007/s11926-017-0660-xDOI Listing
August 2017

Effects of Chondroitinase ABC-Mediated Proteoglycan Digestion on Decellularization and Recellularization of Articular Cartilage.

PLoS One 2016 8;11(7):e0158976. Epub 2016 Jul 8.

Department of Orthopaedics, Warren Alpert Brown Medical School of Brown University/Rhode Island Hospital, Providence, Rhode Island, United States of America.

Articular cartilage has a limited capacity to heal itself and thus focal defects often result in the development of osteoarthritis. Current cartilage tissue engineering strategies seek to regenerate injured tissue by creating scaffolds that aim to mimic the unique structure and composition of native articular cartilage. Decellularization is a novel strategy that aims to preserve the bioactive factors and 3D biophysical environment of the native extracellular matrix while removing potentially immunogenic factors. The purpose of this study was to develop a procedure that can enable decellularization and recellularization of intact articular cartilage matrix. Full-thickness porcine articular cartilage plugs were decellularized with a series of freeze-thaw cycles and 0.1% (w/v) sodium dodecyl sulfate detergent cycles. Chondroitinase ABC (ChABC) was applied before the detergent cycles to digest glycosaminoglycans in order to enhance donor chondrocyte removal and seeded cell migration. Porcine synovium-derived mesenchymal stem cells were seeded onto the decellularized cartilage scaffolds and cultured for up to 28 days. The optimized decellularization protocol removed 94% of native DNA per sample wet weight, while collagen content and alignment were preserved. Glycosaminoglycan depletion prior to the detergent cycles increased removal of nuclear material. Seeded cells infiltrated up to 100 μm into the cartilage deep zone after 28 days in culture. ChABC treatment enhances decellularization of the relatively dense, impermeable articular cartilage by reducing glycosaminoglycan content. ChABC treatment did not appear to affect cell migration during recellularization under static, in vitro culture, highlighting the need for more dynamic seeding methods.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0158976PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4938233PMC
July 2017

Controversial role of arthroscopic meniscectomy of the knee: A review.

World J Orthop 2016 May 18;7(5):287-92. Epub 2016 May 18.

Austin Y Ha, Robert M Shalvoy, Anne Voisinet, Jennifer Racine, Roy K Aaron, Department of Orthopaedic Surgery, Warren Alpert Medical School of Brown University, Providence, RI 02906, United States.

The role of arthroscopic partial meniscectomy (APM) in reducing pain and improving function in patients with meniscal tears remains controversial. Five recent high-quality randomized controlled trials (RCTs) compared non-operative management of meniscal tears to APM, with four showing no difference and one demonstrating superiority of APM. In this review, we examined the strengths and weaknesses of each of these RCTs, with particular attention to the occurrence of inadvertent biases. We also completed a quantitative analysis that compares treatment successes in each treatment arm, considering crossovers as treatment failures. Our analysis revealed that each study was an excellent attempt to compare APM with non-surgical treatment but suffered from selection, performance, detection, and/or transfer biases that reduce confidence in its conclusions. While the RCT remains the methodological gold standard for establishing treatment efficacy, the use of an RCT design does not in itself ensure internal or external validity. Furthermore, under our alternative analysis of treatment successes, two studies had significantly more treatment successes in the APM arm than the non-operative arm although original intention-to-treat analyses showed no difference between these two groups. Crossovers remain an important problem in surgical trials with no perfect analytical solution. With the studies available at present, no conclusion can be drawn concerning the optimal treatment modality for meniscal tears. Further work that minimizes significant biases and crossovers and incorporates sub-group and cost-benefit analyses may clarify therapeutic indications.
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http://dx.doi.org/10.5312/wjo.v7.i5.287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4865718PMC
May 2016

Pathophysiology and risk factors for osteonecrosis.

Curr Rev Musculoskelet Med 2015 Sep;8(3):201-9

Department of Orthopaedics, Warren Alpert Medical School of Brown University, 100 Butler Drive, Providence, RI, 02906, USA,

Osteonecrosis, also known as avascular necrosis or AVN, is characterized by a stereotypical pattern of cell death and a complex repair process of bone resorption and formation. It is not the necrosis itself but rather the resorptive component of the repair process that results in loss of structural integrity and subchondral fracture. Most likely, a common pathophysiological pathway exists involving compromised subchondral microcirculation. Decreased femoral head blood flow can occur through three mechanisms: vascular interruption by fractures or dislocation, intravascular occlusion from thrombi or embolic fat, or intraosseous extravascular compression from lipocyte hypertrophy or Gaucher cells. In this review, we emphasize etiologic relationships derived mostly from longitudinal cohort studies or meta-analyses whose causal relationships to osteonecrosis can be estimated with confidence. Understanding risk factors and pathophysiology has therapeutic implications since several treatment regimens are available to optimize femoral head circulation, interrupt bone resorption, and preserve the subchondral bone.
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http://dx.doi.org/10.1007/s12178-015-9277-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4596210PMC
September 2015

Characterization of bone perfusion by dynamic contrast-enhanced magnetic resonance imaging and positron emission tomography in the Dunkin-Hartley guinea pig model of advanced osteoarthritis.

J Orthop Res 2015 Mar 19;33(3):366-72. Epub 2014 Nov 19.

Department of Radiology, Weill Cornell Medical College, New York City, NY; Citigroup Biomedical Imaging Center, Weill Cornell Medical College, New York City, NY.

This study characterizes changes in subchondral bone circulation in OA and examines relationships to bone structure and cartilage degeneration in Dunkin-Hartley guinea pigs. We have used dynamic contrast-enhanced MRI (DCE-MRI) and PET, with pharmacokinetic modeling, to characterize subchondral bone perfusion. Assessments are made of perfusion kinetics and vascular permeability by MRI, and blood volume and flow, and radionuclide incorporation into bone, by PET. These parameters are compared to cartilage lesion severity and bone histomorphometry. Assessments of intraosseous thrombi are made morphologically. Prolonged signal enhancement during the clearance phase of MRI correlated with OA severity and suggested venous stasis. Vascular permeability was not increased indicating that transvascular migration of contrast agent was not responsible for signal enhancement. Intraosseous thrombi were not observed. Decreased perfusion associated with severe OA was confirmed by PET and was associated with reduced radionuclide incorporation and osteoporosis. MRI and PET can be used to characterize kinetic parameters of circulation in OA and correlate them with subchondral bone metabolism of interest to the pathophysiology of OA. The significance of these observations may lie in alterations induced in the expression of cytokines by OA osteoblasts that are related to bone remodeling and cartilage breakdown.
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http://dx.doi.org/10.1002/jor.22768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4346481PMC
March 2015

Post-traumatic osteoarthritis after ACL injury.

R I Med J (2013) 2014 Nov 3;97(11):25-8. Epub 2014 Nov 3.

Professor of Orthopedic Surgery, Department of Orthopaedics, The Warren Alpert Medical School of Brown University and Director of the Orthopedic Cell Biology Laboratory and the Orthopedic Program in Clinical/Translational Research.

Post-traumatic osteoarthritis (PTOA) occurs as a consequence of joint trauma or occupations or sports that subject joints to excessive loading stresses. Ligament injuries to the knee, particularly tears of the anterior cruciate ligament (ACL), often result in PTOA. Approximately half of the individuals with an ACL injury develop PTOA regardless of the reconstruction of the torn ligament. This observation has raised the possibility that other injuries occur to the knee in association with ACL tears that may involve ligamentous capsular structures, articular cartilage, or subchondral bone. Many ACL injuries occur in noncontact sports and are the result of biomechanical abnormalities. Female athletes are more likely than their male counterparts to suffer ACL injuries. This review outlines the epidemiology of ACL tears, its pathology in cartilage and bone, some of the demographic, biomechanical, and neuromuscular factors involved in ACL tears, and PTOA and important information gained from preclinical injury models.
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November 2014

Sports medicine.

R I Med J (2013) 2014 Nov 3;97(11):17. Epub 2014 Nov 3.

Assistant Professor of Orthopedic Surgery, The Warren Alpert Medical School of Brown University.

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November 2014

Entrainment to a real time fractal visual stimulus modulates fractal gait dynamics.

Hum Mov Sci 2014 Aug 7;36:20-34. Epub 2014 Jun 7.

Gait and Motion Analysis Laboratory, Providence VA Medical Center, Providence, RI, USA.

Fractal patterns characterize healthy biological systems and are considered to reflect the ability of the system to adapt to varying environmental conditions. Previous research has shown that fractal patterns in gait are altered following natural aging or disease, and this has potential negative consequences for gait adaptability that can lead to increased risk of injury. However, the flexibility of a healthy neurological system to exhibit different fractal patterns in gait has yet to be explored, and this is a necessary step toward understanding human locomotor control. Fifteen participants walked for 15min on a treadmill, either in the absence of a visual stimulus or while they attempted to couple the timing of their gait with a visual metronome that exhibited a persistent fractal pattern (contained long-range correlations) or a random pattern (contained no long-range correlations). The stride-to-stride intervals of the participants were recorded via analog foot pressure switches and submitted to detrended fluctuation analysis (DFA) to determine if the fractal patterns during the visual metronome conditions differed from the baseline (no metronome) condition. DFA α in the baseline condition was 0.77±0.09. The fractal patterns in the stride-to-stride intervals were significantly altered when walking to the fractal metronome (DFA α=0.87±0.06) and to the random metronome (DFA α=0.61±0.10) (both p<.05 when compared to the baseline condition), indicating that a global change in gait dynamics was observed. A variety of strategies were identified at the local level with a cross-correlation analysis, indicating that local behavior did not account for the consistent global changes. Collectively, the results show that a gait dynamics can be shifted in a prescribed manner using a visual stimulus and the shift appears to be a global phenomenon.
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http://dx.doi.org/10.1016/j.humov.2014.04.006DOI Listing
August 2014

Design of a biaxial mechanical loading bioreactor for tissue engineering.

J Vis Exp 2013 Apr 25(74):e50387. Epub 2013 Apr 25.

Department of Orthopaedics, The Warren Alpert Brown Medical School of Brown University and the Rhode Island Hospital.

We designed a loading device that is capable of applying uniaxial or biaxial mechanical strain to a tissue engineered biocomposites fabricated for transplantation. While the device primarily functions as a bioreactor that mimics the native mechanical strains, it is also outfitted with a load cell for providing force feedback or mechanical testing of the constructs. The device subjects engineered cartilage constructs to biaxial mechanical loading with great precision of loading dose (amplitude and frequency) and is compact enough to fit inside a standard tissue culture incubator. It loads samples directly in a tissue culture plate, and multiple plate sizes are compatible with the system. The device has been designed using components manufactured for precision-guided laser applications. Bi-axial loading is accomplished by two orthogonal stages. The stages have a 50 mm travel range and are driven independently by stepper motor actuators, controlled by a closed-loop stepper motor driver that features micro-stepping capabilities, enabling step sizes of less than 50 nm. A polysulfone loading platen is coupled to the bi-axial moving platform. Movements of the stages are controlled by Thor-labs Advanced Positioning Technology (APT) software. The stepper motor driver is used with the software to adjust load parameters of frequency and amplitude of both shear and compression independently and simultaneously. Positional feedback is provided by linear optical encoders that have a bidirectional repeatability of 0.1 μm and a resolution of 20 nm, translating to a positional accuracy of less than 3 μm over the full 50 mm of travel. These encoders provide the necessary position feedback to the drive electronics to ensure true nanopositioning capabilities. In order to provide the force feedback to detect contact and evaluate loading responses, a precision miniature load cell is positioned between the loading platen and the moving platform. The load cell has high accuracies of 0.15% to 0.25% full scale.
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http://dx.doi.org/10.3791/50387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3667579PMC
April 2013

Pathogenesis and epidemiology of osteoarthritis.

R I Med J (2013) 2013 Mar 1;96(3):19-22. Epub 2013 Mar 1.

Academic coordinator and research associate in the Department of Orthopaedics.

Osteoarthritis (OA) is a disease of high prevalence that produces substantial morbidity and is a leading cause of physical and psychological disability and expense, including time lost from work, medical care, and disability support. Until recently, the focus of research into the pathophysiology of OA has been on articular cartilage and has not resulted in either biomarkers of OA activity or effective targets for disease-modifying therapy. The contemporary paradigm of OA considers involvement of all joint tissues. It has been shown that, in later-stage OA, bone blood flow and oxygen content are markedly reduced and have a deleterious effect on bone cells, inducing them to release proteins (cytokines) that contribute to the bone remodeling and cartilage breakdown seen in OA.
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March 2013

Corticosteroid-associated avascular necrosis: dose relationships and early diagnosis.

Ann N Y Acad Sci 2011 Dec;1240:38-46

Department of Orthopaedics, Warren Alpert Medical School, Brown University, Providence, Rhode Island, USA.

Corticosteroids are the most common etiological factor in nontraumatic avascular necrosis (AVN) of bone, accounting for about 10% of arthroplasties performed annually in the United States. Evidence is conflicting on the relative importance of peak dose, daily dose, or cumulative dose, and most likely all three represent "high dose" corticosteroid administration and play a role in AVN. The etiology may be multifactorial with corticosteroids superimposed on genetic or pathological predispositions. Joint preservation depends upon early diagnosis and treatment before fracture of the subchondral trabeculae and joint incongruity. Early intervention depends upon identifying at-risk patients and quantifying their risk by understanding clinical and pathophysiological contributions to that risk. Our data and that of others suggest that a screening MRI of at-risk populations will permit detection of AVN at a prefracture stage when preservation of the joint is possible.
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http://dx.doi.org/10.1111/j.1749-6632.2011.06218.xDOI Listing
December 2011

Self-assembled rosette nanotube/hydrogel composites for cartilage tissue engineering.

Tissue Eng Part C Methods 2010 Dec 12;16(6):1233-43. Epub 2010 Apr 12.

Department of Chemistry, Brown University, Providence, Rhode Island, USA.

Recently, hydrogels (alginate, agarose, polyethylene glycol, etc.) have been investigated as promising cartilage-healing materials. To further improve cell-material interactions or mechanical properties of such hydrogel scaffolds, many materials (such as ceramics or carbon nanotubes) have been added to produce composites with tailored properties. In this study, rosette nanotubes (RNTs, self-assembled nanotubes built from DNA base pairs), hydrogels, and cells (specifically, fibroblast-like type-B synoviocytes [SFB cells] and chondrocytes) were combined via a novel electrospinning technique to generate three-dimensional implantable scaffolds for cartilage repair. Importantly, results of this study showed that electrospun RNT/hydrogel composites improved both SFB cell and chondrocyte functions. RNT/hydrogel composites promoted SFB cell chondrogenic differentiation in 2 week culture experiments. Further, studies demonstrated that RNTs enhanced hydrogel adhesive strength to severed collagen. Results of this study thus provided a nanostructured scaffold that enhanced SFB cell adhesion, viability, and chondrogenic differentiation compared to nanosmooth hydrogels without RNTs. This study provided an alternative cartilage regenerative material derived from RNTs that could be directly electrospun into cartilage defects (with SFB cells and/or chondrocytes) to bond to severed collagen and promote cell adhesion, viability, and subsequent functions.
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http://dx.doi.org/10.1089/ten.TEC.2009.0400DOI Listing
December 2010

Using ambulatory virtual environments for the assessment of functional gait impairment: a proof-of-concept study.

Gait Posture 2010 Apr 18;31(4):533-6. Epub 2010 Feb 18.

Virtual Environment Navigation Laboratory (VENLAB), Department of Cognitive & Linguistic Sciences, Brown University, Providence, RI, USA.

This study aimed to demonstrate the sensitivity of virtual reality (VR)/motion tracking to detect global functional gait impairment resulting from an emulated knee disability as a prelude to describing mobility changes following lower limb injury/treatment. Participants walked in a figure-8 around two virtual posts placed 6m apart while viewing the computer-generated environment in a helmet-mounted display. Three-dimensional position and orientation of the participant's head were tracked and used to update the virtual scenes, measure walking path and speed, and control task parameters with real-time feedback. Participants walked with/without an emulated lower extremity disability (splint preventing normal knee flexion). Participants performed the task at self-selected Natural (NAT) speed providing a baseline measure of their turning speed and area. Turning speed and area were then in turn maintained fixed (controlled speed, CS; controlled path, CP) while the other variable was measured as a gait impairment indicator. Different adaptive strategies were used to cope with the emulated deficit during the NAT scenario: maintaining turning speed while altering path geometry; decreasing turning speed while maintaining path geometry; and combining the previous two strategies. This resulted, on average, in decreased turning speeds and increased turning areas. The CS and CP manipulations respectively generated even greater turning areas and more consistent speed decreases. The three subtests acted as intertwined filters enabling the detection of functional gait impairment in all subjects regardless of their adaptive strategies. This proof-of-concept study demonstrated how VR/motion tracking technology can be used to detect and quantitatively characterize global functional mobility impairment.
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http://dx.doi.org/10.1016/j.gaitpost.2010.01.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2854238PMC
April 2010

Nanotextured titanium surfaces for enhancing skin growth on transcutaneous osseointegrated devices.

Acta Biomater 2010 Jun 11;6(6):2352-62. Epub 2009 Dec 11.

Division of Engineering, Brown University, Providence, RI 02912, USA.

A major problem with transcutaneous osseointegrated implants is infection, mainly due to improper closure of the implant-skin interface. Therefore, the design of transcutaneous osseointegrated devices that better promote skin growth around these exit sites needs to be examined and, if successful, would clearly limit infection. Due to the success already demonstrated for orthopedic implants, developing surfaces with biologically inspired nanometer features is a design criterion that needs to be investigated for transcutaneous devices. This study therefore examined the influence of nanotextured titanium (Ti) created through electron beam evaporation and anodization on keratinocyte (skin-forming cell) function. Electron beam evaporation created Ti surfaces with nanometer features while anodization created Ti surfaces with nanotubes. Conventional Ti surfaces were largely micron rough, with few nanometer surface features. Results revealed increased keratinocyte adhesion in addition to increased keratinocyte spreading and differences in keratinocyte filopodia extension on the nanotextured Ti surfaces prepared by either electron beam evaporation or anodization compared to their conventional, unmodified counterparts after 4h. Results further revealed increased keratinocyte proliferation and cell spreading over 3 and 5days only on the nanorough Ti surfaces prepared by electron beam evaporation compared to both the anodized nanotubular and unmodified Ti surfaces. Therefore, the results from this in vitro study provided the first evidence that nano-modification techniques should be further researched as a means to possibly improve skin growth, thereby improving transcutaneous osseointegrated orthopedic implant longevity.
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http://dx.doi.org/10.1016/j.actbio.2009.12.016DOI Listing
June 2010

Orthopaedic war injuries: recent developments in treatment and research.

Instr Course Lect 2009 ;58:117-29

Department of Orthopaedic Surgery, Naval Medical Center, San Diego, California, USA.

Musculoskeletal injury is the most common type of injury among survivors of combat trauma, and combat-related trauma is challenging for an orthopaedic surgeon to treat. Methods of treatment are evolving, but significant gaps remain as knowledge of civilian trauma is extrapolated to combat trauma.
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June 2009

CD14-negative isolation enhances chondrogenesis in synovial fibroblasts.

Tissue Eng Part A 2009 Nov;15(11):3261-70

Department of Orthopaedics, Alpert Medical School of Brown University and Center for Restorative and Regenerative Medicine, Providence VA Medical Center and Brown University, Providence, Rhode Island 02903, USA.

Synovial membrane has been shown to contain mesenchymal stem cells. We hypothesized that an enriched population of synovial fibroblasts would undergo chondrogenic differentiation and secrete cartilage extracellular matrix to a greater extent than would a mixed synovial cell population (MSCP). The optimum doses of transforming growth factor beta 1 (TGF-beta1) and insulin-like growth factor 1 (IGF-1) for chondrogenesis were investigated. CD14-negative isolation was used to obtain a porcine cell population enriched in type-B synovial fibroblasts (SFB) from an MSCP. The positive cell surface markers in SFB were CD90, CD44, and cadherin-11. SFB and MSCP were cultured in the presence of 20 ng/mL TGF-beta1 for 7 days, and SFB were demonstrated to have higher chondrogenic potential. Further dose-response studies were carried out using the SFB cells and several doses of TGF-beta1 (2, 10, 20, and 40 ng/mL) and/or IGF-1 (1, 10, 100, and 500 ng/mL) for 14 days. TGF-beta1 supplementation was essential for chondrogenesis and prevention of cell death, whereas IGF-1 did not have a significant effect on the SFB cell number or glycosaminoglycan production. This study demonstrates that the CD14-negative isolation yields an enhanced cell population SFB that is more potent than MSCP as a cell source for cartilage tissue engineering.
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http://dx.doi.org/10.1089/ten.TEA.2008.0273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2792095PMC
November 2009

Assessment of bone perfusion with contrast-enhanced magnetic resonance imaging.

Orthop Clin North Am 2009 Apr;40(2):249-57

Department of Orthopaedic Surgery, Columbia University Medical Center, 622 West 168th Street, PH 1130, New York, NY 10032, USA.

Osteoarthritis and avascular necrosis are common clinical entities with unknown origins. Recently, vascular changes were implicated in the pathogenesis of both conditions. This article discusses the use of novel noninvasive imaging techniques as a means of assessing bone perfusion and quantifying differences seen in osteoarthritis and avascular necrosis. Review of our human data suggests that the MRI contrast dye is retained for longer periods of time, suggesting decreased perfusion out of regions of osteoarthritis and avascular necrosis. Use of such a noninvasive measure of assessing bone perfusion could be useful in the diagnosis, prevention, and treatment of not only osteoarthritis and avascular necrosis but also other entities that affect the musculoskeletal system.
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http://dx.doi.org/10.1016/j.ocl.2008.12.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2760337PMC
April 2009

Orthopaedic war injuries: from combat casualty care to definitive treatment: a current review of clinical advances, basic science, and research opportunities.

Instr Course Lect 2008 ;57:65-86

Department of Orthopaedic Surgery, Naval Medical Center, San Diego, California, USA.

Musculoskeletal war wounds often involve massive injury to bone and soft tissue that differ markedly in character and extent compared with most injuries seen in civilian practice. These complex injuries have challenged orthopaedic surgeons to the limits of their treatment abilities on the battlefield, during medical evacuation, and in subsequent definitive or reconstructive treatment. Newer methodologies are being used in the treatment of these wounds to prevent so-called second hit complications, decrease complications associated with prolonged medical evacuation, reduce the incidence of infection, and restore optimal function. Basic science advances hold the promise of providing foundations for future treatment options that may improve both bone and soft-tissue healing. Research on the treatment of these often devastating wounds also will have broad applicability to trauma resulting from acts of terrorism or from natural disasters.
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September 2008

FBS suppresses TGF-beta1-induced chondrogenesis in synoviocyte pellet cultures while dexamethasone and dynamic stimuli are beneficial.

J Tissue Eng Regen Med 2007 Nov-Dec;1(6):436-42

Department of Orthopaedics, Alpert Medical School of Brown University, Providence, RI, USA.

In vitro cartilage tissue engineering culture systems benefit from a fine balance of biochemical and mechanical components to maintain the chondrocyte phenotype. This balance, however, can be disrupted by using typical methods for cultivating chondrogenic cells in medium supplemented with fetal bovine serum (FBS) and growth factors. Our goal was to determine the effects of fluid-dynamic stimuli, fetal bovine serum and dexamethasone on the chondrogenesis of 14-day synoviocyte pellet cultures in the presence of TGF-beta1. We employed a pellet culture system that provides a highly cellular three-dimensional structure that permits differentiation and extracellular matrix synthesis. Our results indicated that FBS inhibited glycosaminoglycan (GAG) and type II collagen production. Interestingly, the effect of dynamic stimuli was modulated by the presence of FBS; mixed serum-free cultures had increased GAG production, whereas mixed cultures with 10% FBS exhibited less GAG production compared with their static counterparts, possibly due to pronounced suppressive effects of FBS via increased transport. Dexamethasone addition during the first week of culture resulted in enhanced extracellular matrix production and increased cellularity. Moreover, the presence of 10% FBS in addition to ITS(+) and TGF-beta1 did not significantly increase cell proliferation compared with serum-free medium. These results indicate the importance of a comprehensive analysis of growth conditions for each cell culture system.
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http://dx.doi.org/10.1002/term.56DOI Listing
June 2008

Perfusion abnormalities in subchondral bone associated with marrow edema, osteoarthritis, and avascular necrosis.

Ann N Y Acad Sci 2007 Nov;1117:124-37

Department of Orthopaedics, The Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA.

Bone marrow edema is seen in osteoarthritis, avascular necrosis, and other clinical conditions including the bone marrow edema syndrome. Bone marrow edema is associated with bone pain and may be related to the pathophysiology of osteoarthritis. Our hypothesis is that bone marrow edema is associated with a reduction in perfusion in subchondral bone, which contributes to focal and segmental bone necrosis and cartilage breakdown. We further hypothesize that altered fluid dynamics in subchondral bone comprise part of the physicochemical environment to which osteocytes are highly sensitive and alter their cytokine expression profile in response to changes in fluid flow, pressure, and oxygen gradients. We have used contrast-enhanced magnetic resonance imaging with Gd-DTPA to characterize changes in subchondral bone perfusion in two relevant and related models-the Dunkin-Hartley guinea pig model of osteoarthritis and human bone marrow edema associated with osteoarthritis and avascular necrosis. Pharmacokinetic modeling was used to extract dynamic parameters of perfusion. Representative time-intensity curves are derived, which characterize normal bone and bone with marrow edema. Dynamic contrast-enhanced magnetic resonance imaging may be a useful tool for the early diagnosis of bone perfusion abnormalities and may be used to characterize marrow edema associated with a number of clinical conditions. This technique may also shed light on the pathophysiology of subchondral perfusion in osteoarthritis and avascular necrosis.
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http://dx.doi.org/10.1196/annals.1402.069DOI Listing
November 2007

Regenerative medicine for limb trauma.

Med Health R I 2007 Jan;90(1):6-9

Brown Medical School, Providence, RI 02906, USA.

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January 2007

Biohybrid limbs: new materials and new properties.

Med Health R I 2007 Jan;90(1):4-6

Brown Medical School, Center for Restorative and Regenrative Medicine, Providence, RI 02906, USA.

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January 2007

Horizons in prosthesis development for the restoration of limb function.

J Am Acad Orthop Surg 2006 ;14(10 Spec No.):S198-204

Department of Orthopaedics, Brown University, Providence, RI, USA.

The focus of our research program is the restoration of limb function through a biohybrid approach. We consider the limb conceptually as a biohybrid organ consisting of biological tissue, endoprostheses (including neural devices and joint replacements), and exoprostheses. The biohybrid limb maximizes biological function and functional articulations with optimized human-prosthesis interfaces. Our long-term goals are to create biomimetic prostheses, optimized control systems for prostheses, and optimized human-prosthesis interfaces using both limb lengthening and osseointegration techniques.
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http://dx.doi.org/10.5435/00124635-200600001-00043DOI Listing
January 2009

Orthopedic complications of solid-organ transplantation.

Surg Clin North Am 2006 Oct;86(5):1237-55, viii

Department of Orthopaedics, Brown Medical School, 100 Butler Drive, Providence, RI 02906, USA.

Organ transplantation has undeniably increased the longevity and quality of life of patients with end-stage organ failure. Its has, however, introduced the skeletal complications of (1) fragility fractures and decreased bone density due to pretransplant bone loss and immunosuppressive therapy, and (2) avascular necrosis leading to subchondral fracture and secondary osteoarthritis. This article reviews these two skeletal complications of solid-organ transplantation that lead to structural failure of bone and result in significant morbidity and reduced quality of life.
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http://dx.doi.org/10.1016/j.suc.2006.06.014DOI Listing
October 2006

Microencapsulated cells genetically modified to overexpress human transforming growth factor-beta1: viability and functionality in allogeneic and xenogeneic implant models.

Tissue Eng 2006 Jul;12(7):1733-9

Center for Biomedical Engineering, Brown University, Providence, Rhode Island, USA.

This study explores the suitability of using encapsulated genetically modified fibroblasts for orthopedic tissue engineering by examining cell survival and persistence of human transforming growth factor-beta (hTGF-beta) overexpression in xenogeneic and allogeneic implant models. Human wild-type fibroblasts, modified to produce a latent form of hTGF-beta, and murine mutant-type fibroblasts, engineered to release a constitutively active form of hTGF-beta, were encapsulated separately in Ca2+ -alginate microcapsules. Following a percentage viability assessment by MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) test, microcapsules were implanted into either the subcutaneous or intraperitoneal cavities of mice. Explanted encapsulated cells were characterized for percentage viability and subjected to a release study and a viability test 1 week and 3 weeks following implantation, a time frame consistent with the requirement for orthopedic tissue engineering application of this growth factor. On average, percentage viabilities of encapsulated cells were 64%at implantation, 52% at explantation, and 56%after 1 week following either 1- or 3-week explantation. hTGF-beta release declined following in vivo implantation, more so for xenogeneic than allogeneic models, but remained in the clinically attractive range of 2 to 30 ng/(10(6) implanted cells 24 h). This technical platform for hTGF-beta is very encouraging for cartilage regeneration using orthopedic tissue engineering, and further evaluation is warranted.
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http://dx.doi.org/10.1089/ten.2006.12.1733DOI Listing
July 2006

Clinical biophysics: the promotion of skeletal repair by physical forces.

Ann N Y Acad Sci 2006 Apr;1068:513-31

Department of Orthopaedic Surgery, Brown Medical School, 100 Butler Drive, Providence, RI 02906, USA.

Skeletal tissues respond to the physical demands of their environment by altering the synthesis and organization of the extracellular matrix. These observations have major implications for how physical environmental demands result in the clinical observations of atrophy and hypertrophy, and how manipulation of the physical environment can be used therapeutically to stimulate repair. Electrical stimulation will be considered as a paradigm of how musculoskeletal tissues respond to physical stimuli. A model of demineralized bone matrix-induced endochondral ossification has been used because it epitomizes the cell biology of endochondral bone formation in a temporally consistent way. We have studied cartilage and bone matrix production, the temporal locus of cell responsiveness, signal dosimetry, and the synthesis of signaling cytokines (TGF-beta) using biochemical, immunohistochemical, and molecular techniques. Exposure to certain electrical environments enhances chondrocyte differentiation reflected as a temporal acceleration and quantitative increase of cartilage extracellular matrix, earlier onset of osteogenesis, and more mature trabecular bone. The cell pool competent to respond resides in the mesenchymal stage. The enhancement in chondrogenesis is associated with an increase in TGF-beta synthesis mediated at least in part by binding of the transcription factor AP-1 and may be modulated specifically by phosphorylation of JNK. The clinical practice of orthopedics has empirically created a variety of biophysical environments in attempts to optimize skeletal repair. We are beginning to understand the biological effects of biophysical stimulation and are now poised to replace empiricism with treatment paradigms based upon physiologic understandings of dose and biologic response.
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http://dx.doi.org/10.1196/annals.1346.045DOI Listing
April 2006
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