The obesity paradox and ventriculoperitoneal shunting in aneurysmal subarachnoid hemorrhage patients undergoing microsurgical clipping.

BACKGROUND: Aneurysmal subarachnoid hemorrhage (aSAH) can be devastating. Identifying predisposing factors is paramount in reducing aSAH-related mortality. Obesity's negative impact on health is well-established. However, the controversial "obesity paradox" in neurosurgery suggests that obesity may confer a survival advantage in SAH. We hypothesized that obesity would have a negative impact on outcomes following surgical clipping in aSAH. METHODS: A single-institution retrospective review was performed of aSAH patients undergoing surgical clipping from 2017 to 2021. Demographics and clinically relevant variables were collected. Obesity was defined as body mass index >30. Primary outcome was death or severe disability (mRS 4-6) at last follow-up. Secondary outcome was VPS placement. Multivariable Cox proportional-hazards model identified predictors of poor outcome. Kaplan-Meier curves identified survivorship differences between obese and non-obese patients. RESULTS: Poor outcome occurred in 11 of 52 total patients (21.2 %). There were no differences in demographics or distribution of Hunt Hess (HH), modified Fisher Grade (mFG), or external ventricular drain (EVD) placement between obese and non-obese patients. On univariate analysis, hypertension, older age, and non-obesity were predictive of poor outcome. On multivariable analysis, only obesity remained significant, suggesting a protective effect from poor outcome (HR 0.45 [0.21-0.95], p = 0.037). VPS placement occurred in 6 (11.5 %) patients for which obesity was not a significant predictor. CONCLUSIONS: Obesity may have a protective effect against poor outcome following surgical clipping in aSAH. Additionally, obesity does not appear to increase rate of EVD conversion to VPS. Thus, our study suggests that obesity should not preclude patients from open surgical intervention when clinically appropriate.

Prognosticators of Functional Outcome After Supratentorial Minimally Invasive Intracranial Hemorrhage Evacuation With Tubular Retractor Systems.

BACKGROUND AND OBJECTIVES: Prognosticators of good functional outcome after minimally invasive surgical (MIS) intracranial hemorrhage (ICH) evacuation are poorly defined. This study aims to investigate clinical and radiographic prognosticators of poor functional outcome after MIS evacuation of ICH with tubular retractor systems. METHODS: Single-center retrospective review of adult (age ≥18 years) patients who underwent surgical evacuation of a spontaneous supratentorial ICH evacuation using tubular retractors from 2013 to 2022 was performed. Clinical and radiographic factors, such as antiplatelet/anticoagulant use, initial NIH Stroke Scale, ICH score, premorbid modified Rankin Scale (mRS), intraventricular hemorrhage (IVH) severity according to the modified Graeb scale, and preoperative/postoperative ICH volume, were collected. The main outcome was poor functional outcome, defined as mRS score of 4-6 within 1 year postoperatively. RESULTS: Eighty-eight patients were included. Clinical follow-up data were available for 64 (73%) patients. Of those, 43 (67%) had a poor functional outcome. On multivariate Cox regression, postoperative ICH volume ≥15 mL (hazard ratio [HR] = 2.46 [95% CI: 1.25-4.87]; P = .010) and higher modified Graeb score (HR = 1.04 [95% CI: 1-1.1]; P = .035] significantly increased the risk of poor functional outcome. Elevated postoperative ICH volume was predicted by the presence of lobar ICH (vs nonlobar, OR = 3.32 [95% CI: 1.01-11.55]; P = .043) and higher preoperative ICH volume (OR = 1.05 [1.02-1.08]; P < .001). A minimum of 60% ICH evacuation yielded an improvement in mRS 4-6 rates (HR 0.3 [95% CI: 0.1-0.8], P = .013). In patients without IVH and with a >80% ICH evacuation, the rate of mRS 4-6 was 42% compared with 67% in the whole patient sample ( P = .017). CONCLUSION: Increased IVH volumes and residual postoperative ICH volumes are associated with poor functional outcome after MIS ICH evacuation. Postoperative ICH volume was associated with lobar ICH location as well as preoperative ICH volume. These factors may help to prognosticate patient outcomes and improve selection criteria for MIS ICH evacuation techniques.

Validation of a 3D CT imaging method for quantifying implant migration following anatomic total shoulder arthroplasty.

Glenoid component loosening remains a common complication following anatomic total shoulder arthroplasty (TSA); however, plain radiographs are unable to accurately detect early implant migration. The purpose of this study was to validate the accuracy of a method of postoperative, three-dimensional (3D) computed tomography (CT) imaging with metal artifact reduction (MAR) to detect glenoid component migration following anatomic TSA. Tantalum bead markers were inserted into polyethylene glenoid components for implant detection on 3D CT. In-vitro validation was performed using a glenoid component placed into a scapula sawbone and incrementally translated and rotated, with MAR 3D CT acquired at each test position. Accuracy was evaluated by root mean square error (RMSE). In-vivo validation was performed on six patients who underwent anatomic TSA, with two postoperative CT scans acquired in each patient and marker-based radiostereometric analysis (RSA) performed on the same days. Glenoid component migration was calculated relative to a scapular coordinate system for both MAR 3D CT and RSA. Accuracy was evaluated by RMSE and paired Student's t-tests. The largest RMSE on in-vitro testing was 0.24 mm in translation and 0.11° in rotation, and on in-vivo testing was 0.47 mm in translation and 1.04° in rotation. There were no significant differences between MAR 3D CT and RSA measurement methods. MAR 3D CT imaging is capable of quantifying glenoid component migration with a high level of accuracy. MAR 3D CT imaging is advantageous over RSA because it is readily available clinically and can also be used to evaluate the implant-bone interface.

Relationship Between Glenoid Component Shift and Osteolysis After Anatomic Total Shoulder Arthroplasty: Three-Dimensional Computed Tomography Analysis.

BACKGROUND: The purpose of this study was to evaluate glenoid component position and radiolucency following anatomic total shoulder arthroplasty (TSA) using sequential 3-dimensional computed tomography (3D CT) analysis. METHODS: In a series of 152 patients (42 Walch A1, 16 A2, 7 B1, 49 B2, 29 B3, 3 C1, 3 C2, and 3 D glenoids) undergoing anatomic TSA with a polyethylene glenoid component, sequential 3D CT analysis was performed preoperatively (CT1), early postoperatively (CT2), and at a minimum 2-year follow-up (CT3). Glenoid component shift was defined as a change in component version or inclination of ≥3° from CT2 to CT3. Glenoid component central anchor peg osteolysis (CPO) was assessed at CT3. Factors associated with glenoid component shift and CPO were evaluated. RESULTS: Glenoid component shift occurred from CT2 to CT3 in 78 (51%) of the 152 patients. CPO was seen at CT3 in 19 (13%) of the 152 patients, including 15 (19%) of the 78 with component shift. Walch B2 glenoids with a standard component and glenoids with higher preoperative retroversion were associated with a higher rate of shift, but not of CPO. B3 glenoids with an augmented component and glenoids with greater preoperative joint-line medialization were associated with CPO, but not with shift. More glenoid component joint-line medialization from CT2 to CT3 was associated with higher rates of shift and CPO. A greater absolute change in glenoid component inclination from CT2 to CT3 and a combined absolute glenoid component version and inclination change from CT2 to CT3 were associated with CPO. Neither glenoid component shift nor CPO was associated with worse clinical outcomes. CONCLUSIONS: Postoperative 3D CT analysis demonstrated that glenoid component shift commonly occurs following anatomic TSA, with increased inclination the most common direction. Most (81%) of the patients with glenoid component shift did not develop CPO. Longer follow-up is needed to determine the relationships of glenoid component shift and CPO with loosening over time. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Three-dimensional computed tomography analysis of pathologic correction in total shoulder arthroplasty based on severity of preoperative pathology.

BACKGROUND: The purpose of this study was to quantify correction of glenoid deformity and humeral head alignment in anatomic total shoulder arthroplasty as a function of preoperative pathology (modified Walch classification) and glenoid implant type in a clinical cohort using 3-dimensional computed tomography (CT) analysis. METHODS: Patients undergoing anatomic total shoulder arthroplasty with a standard glenoid (SG) (n = 110) or posteriorly stepped augmented glenoid (AG) (n = 62) component were evaluated with a preoperative CT scan and a postoperative CT scan within 3 months of surgery. Glenoid version, inclination, and medial-lateral (ML) joint line position, as well as humeral head alignment, were assessed on both CT scans, with preoperative-to-postoperative changes analyzed relative to pathology and premorbid anatomy based on the modified Walch classification and glenoid implant type. RESULTS: On average, correction to the premorbid ML joint line position was significantly less in type A2 glenoids than in type A1 glenoids (-2.3 ± 2.1 mm vs. 1.1 ± 0.9 mm, P < .001). Correction to premorbid version was not different between type B2 glenoids with AG components and type A1 glenoids with SG components (-1.7° ± 6.6° vs. -1.0° ± 4.0°, P = .57), and the premorbid ML joint line position was restored on average in both groups (0.3 ± 1.6 mm vs. 1.1 ± 0.9 mm, P = .006). Correction to premorbid version was not different between type B3 glenoids with AG components and type A1 glenoids with SG components (-0.6° ± 5.1° vs. -1.0° ± 4.0°, P = .72), but correction relative to the premorbid ML joint line position was significantly less in type B3 glenoids with AG components than in type A1 glenoids with SG components (-2.2 ± 2.1 mm vs. 1.1 ± 0.9 mm, P < .001). Postoperative humeral glenoid alignment was not different in any group comparisons. DISCUSSION: In cases with posterior glenoid bone loss and retroversion (type B2 or B3 glenoids), an AG component can better correct retroversion and the glenoid ML joint line position compared with an SG component, with correction to premorbid version comparable to a type A1 glenoid with an SG component. However, restoration of the premorbid ML joint line position may not always be possible with SG or AG components in cases with more advanced central glenoid bone loss (type A2 or B3 glenoids). Further follow-up is needed to determine the clinical consequences of these findings.

Accuracy of 3-Dimensional Planning, Implant Templating, and Patient-Specific Instrumentation in Anatomic Total Shoulder Arthroplasty.

BACKGROUND: Use of 3-dimensional (3D) computed tomography (CT) preoperative planning and patient-specific instrumentation has been demonstrated to improve the accuracy of glenoid implant placement in total shoulder arthroplasty (TSA). The purpose of this study was to compare the accuracy of glenoid implant placement in primary TSA among different types of instrumentation used with the 3D CT preoperative planning. METHODS: One hundred and seventy-three patients with end-stage glenohumeral arthritis were enrolled in 3 prospective studies evaluating patient-specific instrumentation and 3D preoperative planning. All patients underwent preoperative 3D CT planning to determine optimal glenoid component and guide pin position based on surgeon preference. Patients were placed into 1 of 5 instrument groups used for intraoperative guide pin placement: (1) standard instrumentation, (2) standard instrumentation combined with use of a 3D glenoid bone model containing the guide pin, (3) use of the 3D glenoid bone model combined with single-use patient-specific instrumentation, (4) use of the 3D glenoid bone model combined with reusable patient-specific instrumentation, and (5) use of reusable patient-specific instrumentation with an adjustable, reusable base. Postoperatively, all patients underwent 3D CT to compare actual versus planned glenoid component position. Deviation from the plan (in terms of orientation and location) was compared across groups on the basis of absolute differences and outlier analysis. Univariable and multivariable comparisons were performed. As the initial analyses showed no significant differences in preoperative factors or in deviation from the plan between Groups 1 and 2 or between Groups 4 and 5 across studies, the final analysis was across 3 major treatment groups: standard instrumentation (Groups 1 and 2), single-use patient-specific instrumentation (Group 3), and reusable patient-specific instrumentation (Groups 4 and 5). RESULTS: In nearly all comparisons, there were no significant differences in the deviation from the plan (absolute differences or outlier frequency) for glenoid implant orientation or location across the 3 major treatment groups. CONCLUSIONS: This study did not demonstrate that any type of patient-specific instrumentation resulted in consistent differences in accuracy of glenoid implant placement in primary TSA with 3D CT preoperative planning. Surgeons have multiple patient-specific instrumentation options available for improving accuracy of glenoid implant placement when compared with 2D imaging without patient-specific instrumentation. LEVEL OF EVIDENCE: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

Scapular Notching After Reverse Total Shoulder Arthroplasty: Prediction Using Patient-Specific Osseous Anatomy, Implant Location, and Shoulder Motion.

BACKGROUND: Scapular notching is frequently observed following reverse total shoulder arthroplasty (rTSA), although the etiology is not well understood. METHODS: Twenty-nine patients with preoperative computed tomography (CT) scans who underwent rTSA with a Grammont design were evaluated after a minimum of 2 years of follow-up with video motion analysis (VMA), postoperative three-dimensional (3D) CT, and standard radiographs. The glenohumeral range of motion demonstrated by the VMA and the postoperative implant location on the CT were used in custom simulation software to determine areas of osseous impingement between the humeral implant and the scapula and their relationship to scapular notching on postoperative CT. Patients with and without notching were compared with one another by univariable and multivariable analyses to determine factors associated with notching. RESULTS: Seventeen patients (59%) had scapular notching, which was along the posteroinferior aspect of the scapular neck in all of them and along the anteroinferior aspect of the neck in 3 of them. Osseous impingement occurred in external rotation with the arm at the side in 16 of the 17 patients, in internal rotation with the arm at the side in 3, and in adduction in 12. The remaining 12 patients did not have notching or osseous impingement. Placing the glenosphere in a position that was more inferior (by a mean of 3.4 ± 2.3 mm) or lateral (by a mean of 6.2 ± 1.4 mm) would have avoided most impingement in the patients' given range of motion. Notching was associated with glenosphere placement that was insufficiently inferior (mean inferior translation, -0.3 ± 3.4 mm in the notching group versus 3.0 ± 2.9 mm in the no-notching group; p = 0.01) or posterior (mean, -0.3 ± 3.5 mm versus 4.2 ± 2.2 mm; p < 0.001). Two-variable models showed inferior and posterior (area under the curve [AUC], 0.887; p < 0.001), inferior and lateral (AUC, 0.892; p < 0.001), and posterior and lateral (AUC, 0.892; p < 0.001) glenosphere positions to be significant predictors of the ability to avoid scapular notching. CONCLUSIONS: Osseous impingement identified using patients' actual postoperative range of motion and implant position matched the location of scapular notching seen radiographically. Inferior, lateral, and posterior glenosphere positions are all important factors in the ability to avoid notching. Only small changes in implant position were needed to avoid impingement, suggesting that preoperative determination of the ideal implant position may be a helpful surgical planning tool to avoid notching when using this implant design. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Sequential 3-dimensional computed tomography analysis of implant position following total shoulder arthroplasty.

BACKGROUND: Detection of postoperative component position and implant shift following total shoulder arthroplasty (TSA) can be challenging using routine imaging. The purpose of this study was to evaluate glenoid component position over time using 3-dimensional computed tomography (CT) analysis with minimum 2-year follow-up. METHODS: Twenty patients underwent primary TSA with sequential CT scanning of the shoulder: a preoperative study, an immediate postoperative study within 2 weeks of surgery, and a postoperative study performed at minimum 2-year follow-up (CT3). Postoperative glenoid component position and central peg osteolysis were assessed across the immediate postoperative CT scan and CT3. Glenoids with evidence of component shift and/or grade 1 central peg osteolysis on CT3 were considered at risk of loosening. RESULTS: Of the patients, 7 (35%) showed evidence of glenoid components at risk of loosening on CT3, 6 with component shift (3 with increased inclination alone, 1 with increased retroversion alone, and 2 with both increased inclination and retroversion). Significantly more patients with glenoid component shift had grade 1 central peg osteolysis on CT3 compared with those without shift (83% vs 7%, P = .002). One clinical failure occurred, with the patient undergoing revision to reverse TSA for rotator cuff deficiency. CONCLUSIONS: Three-dimensional CT imaging analysis following TSA identified changes in glenoid component position over time, with inclination being the most common direction of shift and grade 1 central peg osteolysis commonly associated with shift. These findings raise concern for glenoids at risk of loosening, but further follow-up is needed to determine the long-term clinical impact of these findings.

The Efficiency of Bone Marrow Aspiration for the Harvest of Connective Tissue Progenitors from the Human Iliac Crest.

BACKGROUND: The rational design and optimization of tissue engineering strategies for cell-based therapy requires a baseline understanding of the concentration and prevalence of osteogenic progenitor cell populations in the source tissues. The aim of this study was to (1) define the efficiency of, and variation among individuals in, bone marrow aspiration as a means of osteogenic connective tissue progenitor (CTP-O) harvest compared with harvest from iliac cancellous bone, and (2) determine the location of CTP-Os within native cancellous bone and their distribution between the marrow-space and trabecular-surface tissue compartments. METHODS: Eight 2-mL bone marrow aspiration (BMA) samples and one 7-mm transcortical biopsy sample were obtained from the anterior iliac crest of 33 human subjects. Two cell populations were obtained from the iliac cancellous bone (ICB) sample. The ICB sample was placed into αMEM (alpha-minimal essential medium) with antibiotic-antimycotic and minced into small pieces (1 to 2 mm in diameter) with a sharp osteotome. Cells that could be mechanically disassociated from the ICB sample were defined as marrow-space (IC-MS) cells, and cells that were disassociated only after enzymatic digestion were defined as trabecular-surface (IC-TS) cells. The 3 sources of bone and marrow-derived cells were compared on the basis of cellularity and the concentration and prevalence of CTP-Os through colony-forming unit (CFU) analysis. RESULTS: Large variation was seen among patients with respect to cell and CTP-O yield from the IC-MS, IC-TS, and BMA samples and in the relative distribution of CTP-Os between the IC-MS and IC-TS fractions. The CTP-O prevalence was highest in the IC-TS fraction, which was 11.4-fold greater than in the IC-MS fraction (p < 0.0001) and 1.7-fold greater than in the BMA fraction. However, the median concentration of CTP-Os in the ICB (combining MS and TS fractions) was only 3.04 ± 1.1-fold greater than that in BMA (4,265 compared with 1,402 CTP/mL; p = 0.00004). CONCLUSIONS: Bone marrow aspiration of a 2-mL volume at a given needle site is an effective means of harvesting CTP-Os, albeit diluted with peripheral blood. However, the median concentration of CTP-Os is 3-fold less than from native iliac cancellous bone. The distribution of CTP-Os between the IC-MS and IC-TS fractions varies widely among patients. CLINICAL RELEVANCE: Bone marrow aspiration is an effective means of harvesting CTP-Os but is associated with dilution with peripheral blood. Overall, we found that 63.5% of all CTP-Os within iliac cancellous bone resided on the trabecular surface; however, 48% of the patients had more CTP-Os contributed by the IC-MS than the IC-TS fraction.

Quantitative Measurement of Osseous Pathology in Advanced Glenohumeral Osteoarthritis.

BACKGROUND: Osteoarthritis of the glenohumeral joint has typical patterns of deformity as described by Walch et al. However, more severe glenoid pathology may be difficult to classify. The purpose of this study was to use 3-dimensional computed tomography (3-D CT) imaging analysis to define common pathologic subtypes that can be differentiated from the current Walch classification. METHODS: We performed quantitative measurements of premorbid and pathologic anatomy using preoperative 3-D CT scans from 155 cases of advanced glenohumeral osteoarthritis that underwent anatomic or reverse total shoulder arthroplasty. We defined premorbid glenohumeral anatomy on the basis of previously validated methods using 3-D glenoid vault and humeral best-fit circle models including the premorbid glenoid version, joint-line medialization, and humeral-glenoid alignment (HGA). We determined the anatomic features that differentiate new glenoid morphologic subtypes from the existing Walch classification both qualitatively and quantitatively. RESULTS: We defined 2 new glenoid subtypes (B3 and C2) for which the glenoid pathology and humeral alignment were not defined in the original Walch classification. The B3 glenoid has high pathologic retroversion, normal premorbid version, and acquired central and posterior bone loss that, on average, is greater than that of the B2 glenoid. The C2 glenoid is dysplastic with high pathologic retroversion, high premorbid version, and acquired posterior bone loss, giving it the appearance of a biconcave glenoid with posterior translation of the humeral head. This C2 glenoid can be confused with the B2 glenoid. CONCLUSIONS: The B3 and C2 patterns have qualitative and quantitative differences that may result in different clinical outcomes than classic B2 or C types; therefore, our findings suggest that these new subtypes should be included in a new or modified classification system.

Three-dimensional imaging and templating improve glenoid implant positioning.

BACKGROUND: Preoperative quantitative assessment of glenoid bone loss, selection of the glenoid component, and definition of its desired location can be challenging. Placement of the glenoid component in the desired location at the time of surgery is difficult, especially with severe glenoid pathological conditions. METHODS: Forty-six patients were randomly assigned to three-dimensional computed tomographic preoperative templating with either standard instrumentation or with patient-specific instrumentation and were compared with a nonrandomized group of seventeen patients with two-dimensional imaging and standard instrumentation used as historical controls. All patients had postoperative three-dimensional computed tomographic metal artifact reduction imaging to measure and to compare implant position with the preoperative plan. RESULTS: Using three-dimensional imaging and templating with or without patient-specific instrumentation, there was a significant improvement achieving the desired implant position within 5° of inclination or 10° of version when compared with two-dimensional imaging and standard instrumentation. CONCLUSION: Three-dimensional assessment of glenoid anatomy and implant templating and the use of these images at the time of surgery improve the surgeon's ability to place the glenoid implant in the desired location.

Slowing the Onset of Hypoxia Increases Colony Forming Efficiency of Connective Tissue Progenitor Cells In Vitro.

BACKGROUND: Survival and colony formation by transplanted tissue derived connective tissue progenitor cells (CTPs) are thought to be important factors in the success of clinical tissue engineering strategies for bone regeneration. Transplantation of cells into defects larger than a few millimeters expose cells to a profoundly hypoxic environment. This study tested the hypothesis that delaying the onset of hypoxia will improve the survival and performance of CTPs in vitro. METHODS: To mimic declines seen in an avascular in vivo bone defect, colony forming efficiency by marrow derived nucleated cells was assessed under osteogenic conditions. Variation in the rate of oxygen decline from an oxygen tension of 21% to 0.1% oxygen was explored using an incubator with programmable active control of gas concentrations. The effect of doping cultures with defined concentrations of RBCs was also used to evaluate the potential for RBCs to serve as a natural buffer in the setting of declining oxygen levels. RESULTS: A delay in onset of hypoxia over 96 hours resulted in a 3-fold increase in the relative colony forming efficiency (rCFE) of CTPs as compared to an immediate onset of hypoxia. The presence of RBCs in vitro inhibited the rCFE of CTPs. Given the negative effects of RBCs, methods of RBC removal were evaluated and compared for their effectiveness of RBC removal and retention of colony forming efficiency. CONCLUSIONS: These data suggest that conditions of hypoxia compromise colony forming efficiency in marrow derived CTPs. However, slowing the rate of decline of oxygen preserved colony forming efficiency at levels achieved in a stable normoxic (3% O2) environment. These data also suggest that RBCs are detrimental to the rCFE of CTPs and that buffy coat is an effective and preferred method for removing RBCs from marrow aspirates while preserving CTPs. These findings may inform clinical strategies for CTP transplantation.

The design and use of animal models for translational research in bone tissue engineering and regenerative medicine.

This review provides an overview of animal models for the evaluation, comparison, and systematic optimization of tissue engineering and regenerative medicine strategies related to bone tissue. This review includes an overview of major factors that influence the rational design and selection of an animal model. A comparison is provided of the 10 mammalian species that are most commonly used in bone research, and existing guidelines and standards are discussed. This review also identifies gaps in the availability of animal models: (1) the need for assessment of the predictive value of preclinical models for relative clinical efficacy, (2) the need for models that more effectively mimic the wound healing environment and mass transport conditions in the most challenging clinical settings (e.g., bone repair involving large bone and soft tissue defects and sites of prior surgery), and (3) the need for models that allow more effective measurement and detection of cell trafficking events and ultimate cell fate during the processes of bone modeling, remodeling, and regeneration. The ongoing need for both continued innovation and refinement in animal model systems, and the need and value of more effective standardization are reinforced.

Cellular strategies for enhancement of fracture repair.

Tissue engineering seeks to translate scientific knowledge into tangible products to advance the repair, replacement, or regeneration of organs and tissues. Current tissue engineering strategies have progressed recently from a historical approach that is based primarily on biomaterials to a cell and tissue-based approach that includes understanding of cell-sourcing and bioactive stimuli. New options include methods for harvest and transplantation of tissue-forming cells, bioactive matrix materials that act as tissue scaffolds, and delivery of bioactive molecules within scaffolds. These strategies are already benefiting patients, and they place increasing demands on orthopaedic surgeons to have a solid foundation in the contemporary concepts and principles of cell-based tissue engineering. Essentially all orthopaedic tissue engineering strategies can be distilled to a strategy or combination of strategies that seek to increase the number or relative performance of bone-forming cells. The global term connective tissue progenitors has been used to define the heterogeneous populations of stem and progenitor cells that are found in native tissue and that are capable of differentiating into one or more connective tissue phenotypes. These stem or progenitor populations are found in various tissue sources, with varying degrees of ability to differentiate along connective tissue lineages. Available cell-based strategies include targeting local cells with use of scaffolds or bioactive factors, or transplantation of autogenous connective tissue progenitor cells derived from bone marrow or other tissues, with or without processing to change their concentration or prevalence. The future may include means of homing circulating connective tissue progenitor cells with use of intrinsic chemokine systems, or modifying the biological performance of connective tissue progenitor cells by means of genetic modifications.

Decibel attenuation of pulsed electromagnetic field (PEMF) in blood and cortical bone determined experimentally and from the theory of ohmic losses.

We studied the PEMF power attenuation in tissues representative of clinical applications (blood and cortical bone) to determine the amount of power available for PEMF purported biological effects. The experimental system consisted of a pair of nearly circular, parallel and coaxial coils separated by a distance of one coil diameter. The power attenuation was measured using a small search coil connected to a digital oscilloscope. The coils were powered by a voltage switch operating at two different frequencies (3.8 and 63 kHz) producing bursts of pulses (numbering 21 and 1619) and triggered at two different frequencies (1.5 and 15 Hz, respectively). The tissue samples were placed inside the coils so as to expose them to either transverse electric field (at the center of coils) or the transverse magnetic field (at the coil wire). The cylindrical coil geometry yielded closed-form expressions for power attenuation based on magnetic diffusion equation and ohmic losses due to bulk tissue magnetic permeability and electrical conductivity. The measured power attenuation at these PEMF frequencies of not more than one decibel (1 dB) was well explained by the theory for the 3.8 kHz but less so for the 63 kHz frequency PEMF. The results provide important insights regarding physical mechanism of weak PEMF power dissipation in tissues.

Exposure of murine cells to pulsed electromagnetic fields rapidly activates the mTOR signaling pathway.

Murine pre-osteoblasts and fibroblast cell lines were used to determine the effect of pulsed electromagnetic field (PEMF) exposure on the production of autocrine growth factors and the activation of early signal transduction pathways. Exposure of pre-osteoblast cells to PEMF minimally increased the amount of secreted TGF-beta after 1 day, but had no significant effects thereafter. PEMF exposure of pre-osteoblast cells also had no effect on the amount of prostaglandin E(2) in the conditioned medium. Exposure of both pre-osteoblasts and fibroblasts to PEMF rapidly activated the mTOR signaling pathway, as evidenced by increased phosphorylation of mTOR, p70 S6 kinase, and the ribosomal protein S6. Inhibition of PI3-kinase activity with the chemical inhibitor LY294002 blocked PEMF-dependent activation of mTOR in both the pre-osteoblast and fibroblast cell lines. These findings suggest that PEMF exposure might function in a manner analogous to soluble growth factors by activating a unique set of signaling pathways, inclusive of the PI-3 kinase/mTOR pathway.

Exposure of mouse preosteoblasts to pulsed electromagnetic fields reduces the amount of mature, type I collagen in the extracellular matrix.

We tested the hypothesis that exposure of a mouse preosteoblast cell line to pulsed electromagnetic fields (PEMF) would affect components of the extracellular matrix. We report that exposure of MC3T3-E1 cells to a single PEMF waveform significantly reduced the amount of mature, alpha1(I) collagen in the extracellular matrix (ECM) and the conditioned medium, without affecting the amount of total ECM protein. This decrease was not due to changes in the steady-state level of Col1A1 mRNA or to degradation of mature collagen. We then tested the effect of three distinct PEMF waveforms, two orthogonal coil orientations, and two waveform amplitude levels on the amount of alpha1(I) collagen in the conditioned medium. A sequence of factorial ANOVAs and stepwise regression modeling revealed that the period (duration) of the individual pulses accounted for a significant proportion of the variance associated with the amount of alpha1(I) collagen in the conditioned medium. The total variance accounted for, however, was small (R(2)=0.155, p<0.001 and R(2)=0.172, p<0.001, in the horizontal and vertical orientations, respectively). The positive and negative regression coefficients for the coil orientations revealed that the influence of pulse period was significantly different for the orthogonal coil orientations (p<0.001). The findings imply that the dominant influence of PEMF on the amount of mature, alpha1(I) collagen in the ECM is related to variables other than those expressed in the time-amplitude domain. The results provide objective direction toward identifying waveform characteristics that contribute to the observed between-waveform differences with regard to collagen. Advances in this area may lead toward improving waveforms and waveform delivery protocols.

Pulsed electromagnetic field treatments enhance the healing of fibular osteotomies.

This study tested the hypothesis that pulsed electromagnetic field (PEMF) treatments augment and accelerate the healing of bone trauma. It utilized micro-computed tomography imaging of live rats that had received bilateral 0.2 mm fibular osteotomies (approximately 0.5% acute bone loss) as a means to assess the in vivo rate dynamics of hard callus formation and overall callus volume. Starting 5 days post-surgery, osteotomized right hind limbs were exposed 3 h daily to Physio-Stim PEMF, 7 days a week for up to 5 weeks of treatment. The contralateral hind limbs served as sham-treated, within-animal internal controls. Although both PEMF- and sham-treatment groups exhibited similar onset of hard callus at approximately 9 days after surgery, a 2-fold faster rate of hard callus formation was observed thereafter in PEMF-treated limbs, yielding a 2-fold increase in callus volume by 13-20 days after surgery. The quantity of the new woven bone tissue within the osteotomy sites was significantly better in PEMF-treated versus sham-treated fibulae as assessed via hard tissue histology. The apparent modulus of each callus was assessed via a cantilever bend test and indicated a 2-fold increase in callus stiffness in the PEMF-treated over sham-treated fibulae. PEMF-treated fibulae exhibited an apparent modulus at the end of 5-weeks that was approximately 80% that of unoperated fibulae. Overall, these data indicate that Physio-Stim PEMF treatment improved osteotomy repair. These beneficial effects on bone healing were not observed when a different PEMF waveform, Osteo-Stim, was used. This latter observation demonstrates the specificity in the relationship between waveform characteristics and biological outcomes.

Bone mass is preserved in a critical-sized osteotomy by low energy pulsed electromagnetic fields as quantitated by in vivo micro-computed tomography.

The effectiveness of non-invasive pulsed electromagnetic fields (PEMF) on stimulating bone formation in vivo to augment fracture healing is still controversial, largely because of technical ambiguities in data interpretation within several previous studies. To address this uncertainty, we implemented a rigorously controlled, blinded protocol using a bilateral, mid-diaphyseal fibular osteotomy model in aged rats that achieved a non-union status within 3-4 weeks post-surgery. Bilateral osteotomies allowed delivery of a PEMF treatment protocol on one hind limb, with the contralateral limb representing a within-animal sham-treatment. Bone volumes in both PEMF-treated and sham-treated fibulae were assessed simultaneously in vivo using highly sensitive, high-resolution micro-computed tomography (microCT) over the course of treatment. We found a significant reduction in the amount of time-dependent bone volume loss in PEMF-treated, distal fibular segments as compared to their contralateral sham-treated bones. Osteotomy gap size was significantly smaller in hind limbs exposed to PEMF over sham-treatment. Therefore, our data demonstrate measurable biological consequences of PEMF exposure on in vivo bone tissue.