Christopher P. Geffre

Bone cancer pain

In the United States, cancer is the second most common cause of death and it is expected that about 562,340 Americans will have died of cancer in 2009. Bone cancer pain is common in patients with advanced breast, prostate, and lung cancer as these tumors have a remarkable affinity to metastasize to bone. Once tumors metastasize to bone, they are a major cause of morbidity and mortality as the tumor induces significant skeletal remodeling, fractures, pain, and anemia. Currently, the factors that drive cancer pain are poorly understood. However, several recently introduced models of bone cancer pain, which closely mirror the human condition, are providing insight into the mechanisms that drive bone cancer pain and guide the development of mechanism‐based therapies to treat the cancer pain. Several of these mechanism‐based therapies have now entered human clinical trials. If successful, these therapies have the potential to significantly enlarge the repertoire of modalities that can be used to treat bone cancer pain and improve the quality of life, functional status, and survival of patients with bone cancer.

Targeting integrin α6 stimulates curative-type bone metastasis lesions in a xenograft model.

Laminin-binding integrin receptors are key mediators of epithelial cell migration and tumor metastasis. Recent studies have demonstrated a role for the α6 integrin (ITGA6/CD49f) in maintaining stem cell compartments within normal bone marrow and in residency of tumors metastatic to bone. In this study, we tested a function-blocking antibody specific for ITGA6, called J8H, to determine if preexisting cancer lesions in bone could be slowed and/or animal survival improved. Human prostate tumors were established by intracardiac injection into male SCID mice and treatment with J8H antibody was initiated after 1 week. Tumor progression was monitored by micro-computed tomography (CT) imaging of skeletal lesions. Animals that received weekly injections of the anti-ITGA6 antibody showed radiographic progression in only 40% of osseous tumors (femur or tibia), compared with control animals, where 80% of the lesions (femur or tibia) showed progression at 5 weeks. Kaplan–Meier survival analysis demonstrated a significant survival advantage for J8H-treated animals. Unexpectedly, CT image analysis revealed an increased proportion of bone lesions displaying a sclerotic rim of new bone formation, encapsulating the arrested lytic lesions in animals that received the anti-ITGA6 antibody treatment. Histopathology of the sclerotic lesions demonstrated well-circumscribed tumor within bone, surrounded by fibrosis. These data suggest that systemic targeting of the ITGA6-dependent function of established tumors in bone may offer a noncytotoxic approach to arrest the osteolytic progression of metastatic prostate cancer, thereby providing a new therapeutic strategy for advanced disease. Mol Cancer Ther; 13(6); 1558–66. ©2014 AACR.

A novel biomimetic polymer scaffold design enhances bone ingrowth

There has been recent interest in treating large bone defects with polymer scaffolds because current modalities such as autographs and allographs have limitations. Additionally, polymer scaffolds are utilized in tissue engineering applications to implant and anchor tissues in place, promoting integration with surrounding native tissue. In both applications, rapid and increased bone growth is crucial to the success of the implant. Recent studies have shown that mimicking native bone tissue morphology leads to increased osteoblastic phenotype and more rapid mineralization. The purpose of this study was to compare bone ingrowth into polymer scaffolds created with a biomimetic porous architecture to those with a simple porous design. The biomimetic architecture was designed from the inverse structure of native trabecular bone and manufactured using solid free form fabrication. Histology and muCT analysis demonstrated a 500-600% increase in bone growth into and adjacent to the biomimetic scaffold at five months post-op. This is in agreement with previous studies in which biomimetic approaches accelerated bone formation. It also supports the applicability of polymer scaffolds for the treatment of large tissue defects when implanting tissue-engineering constructs. (c) 2008 Wiley Periodicals, Inc. J Biomed Mater Res, 2009.

Biomechanical evaluation of suture-augmented locking plate fixation for proximal third fractures of the olecranon.

Objectives: To describe a method of suture augmentation of locking plate fixation (PF) of proximal olecranon fractures and to evaluate the biomechanical effectiveness of the suture augmentation using a human cadaveric model. Methods: Six matched pairs of cadaveric elbows were used. Proximal one-third fractures of the olecranon were simulated via a transverse osteotomy. Identical locking PF was performed on each elbow using olecranon locking plates. One elbow of each pair was assigned to suture augmentation of the construct. The choice of left/right specimen for augmentation was performed in an alternating fashion. Augmentation was performed using a no. 2 ultra-high–molecular weight polyethylene–braided suture attaching the triceps to the plate via a modified Krackow stitch. The elbows were mounted into a custom jig and linearly loaded to failure using a hydraulic testing machine. Load to and modes of failure were recorded for each sample. The data were analyzed using the Wilcoxon signed-rank test for nonparametric distributions. Results: Suture augmentation improved the single load-to-failure strength in all pairs. One pair was excluded due to failure of the triceps attachment to the test machine. A median 398 N (P = 0.04 range, 197–633 N) or a median 48% (range, 30%–130%) improvement in strength was seen. The most common mode of failure was loss of fixation of the proximal olecranon fragment. Conclusions: Suture augmentation can significantly increase the single load-to-failure strength of locking PF for proximal olecranon fractures.

Evaluation of the Osteogenic Performance of Calcium Phosphate-Chitosan Bone Fillers

ABSTRACT There has been recent interest in utilizing calcium phosphates (CaPs) that set in situ for treating bone defects due to the limitations associated with morselized autografts and allografts. However, CaP cements have long setting times, poor mechanical properties, and poor osteoinductivity. This has prompted research toward finding a nonprotein-based compound, such as chitosan, to accelerate setting times and increase osteoinductivity. The purpose of this study was to compare bone growth rates during the early bone healing response achieved using conventionally prepared chitosan-CaP bone filler to an extensively purified chitosan-CaP compound. Both compounds set quickly and stimulated bone formation. Histomorphometry demonstrated a 290% increase in new bone formation when using the conventional chitosan-CaP bone filler and a 172% increase with the highly purified chitosan-CaP compound compared to the increase in bone formation seen with the unfilled control group. The results of this study indicate that a highly purified chitosan-CaP paste stimulated less bone formation than a conventionally prepared chitosan-CaP paste but both pastes have the potential to stimulate bone formation.

In vivo telemetric determination of shear and axial loads on a regenerative cartilage scaffold following ligament disruption

Recent interest in repair of chondral and osteochondral cartilage defects to prevent osteoarthritis caused by ligament disruption has led to the research and development of biomimetic scaffolds combined with cell-based regeneration techniques. Current clinical focal defect repair strategies have had limited success. New scaffold-based approaches may provide solutions that can repair extensive damage and prevent osteoarthritis. This study utilized a novel scaffold design that accommodated strain gauges for shear and axial load monitoring in the canine stifle joint through implantable telemetry technology. Loading changes induced by ligament disruption are widely implicated in the development of injury-related osteoarthritis. Seeding the scaffold end with progenitor cells resulted in higher shear stress than without cell seeding and histology showed significantly more bone and cartilage formation. Biomechanically, the effect of transecting the anterior cruciate ligament was a significant reduction in braking load in shear, but no change axially, and conversely a significant reduction in push-off load axially, but no change in shear. This is the first study to report shear loads measured directly in knee joint tissue. Further, advances of these measurement techniques are critical to developing improved regeneration strategies and personalizing reliable rehabilitation protocols.

Load Measurement Accuracy from Sensate Scaffolds with and without a Cartilage Surface

ABSTRACT The use of “sensate” scaffolds covered with tissue-engineered cartilage has emerged as a possible treatment option for focal articular cartilage defects. The ability to monitor joint loading provides several benefits that can be useful in both clinical and research situations. Previous studies have shown that these scaffolds can accurately monitor in vivo joint loading during various activities. However, the effect that an articular cartilage layer or soft tissue overgrowth has on scaffold sensitivity has not been tested. Eight scaffolds were tested with cartilage samples taken from four hounds. Three strain gauges were attached to each scaffold and a servo hydraulics system was used to test sensitivity while the scaffold was in contact with cartilage, metal, or silicone surfaces. Strain gauge sensitivity was calculated from load and strain measurements collected during testing. There was no significant difference between the mean strain gauge sensitivities when the scaffolds were in contact with the different surfaces: cartilage 30.9 ± 16.2 με/N, metal 31.8 ± 18.6 με/N, and silicone 30.6 ± 12.3 με/N. These results indicate that “sensate” scaffolds can be calibrated and used to monitor load with the presence of an articular cartilage layer.

Co-Culture of Adipose Derived Stem Cells and Chondrocytes with Surface Modifying Proteins Induces Enhanced Cartilage Tissue Formation

ABSTRACT Objectives: Current treatments for focal cartilage defects include osteochondral allograft transplants—a common treatment for large defects and revisions of previously autografted joints. Allografts with weak osseous regions are usable, since bone remodeling replaces inferior quality bone. However, poor quality chondral surfaces on grafts preclude their use, leading to grafting material shortages. Endogenous adult stem cells can make hyaline-like cartilage tissue on scaffolds. To increase the number of usable allografts, tissue culture methods using adipose derived stem cells (ASCs) were developed to grow cartilage on grafts. Methods: Co-cultures utilized living chondrocytes in host cartilage, modeling in vivo conditions, and ASCs seeded on the allografts. Sterilized allografts were treated with Poly-L-Lysine and ProNectin. Tissue growth was analyzed and quantified with histological techniques. Results and Conclusions: Monoculture experiments produced tenuous cartilage formation when proteins were utilized and allograft surfaces were perforated. Extensive tissue formation was observed with co-culture and the presence of type II collagen was confirmed with immunohistochemistry. Results demonstrate that co-culture techniques offer a better means of growing tissue on allograft cartilage surfaces. Additionally, the use of proteins to facilitate surface attachment produced more tissue formation demonstrating that cell attachment is crucial when growing cartilage on allografts. Development of new culture techniques to evaluate treatment strategies will accelerate the rate at which cartilage procedures using endogenous cells are possible. This will increase the number of usable grafts and allow critical selection of grafts to fit specific surfaces increasing surgical success by returning the joint to its native structure.

MRI of ovarian torsion: Correlation of imaging features with the presence of perifollicular hemorrhage and ovarian viability

PURPOSE The purpose of our study is to test for: (a) correlation between the presence of a perifollicular T2-hypointense rim on MRI with the presence of perifollicular hemorrhage on histology; and (b) correlation between this finding and diminished ovarian viability after intra-operative detorsion. METHODS AND MATERIALS Our IRB-approved, retrospective study evaluated 780 patients between August 2012 and February 2016 with ovarian torsion as a diagnostic consideration on the emergency department note. Patients were included if they had preoperative MRI and intraoperatively confirmed case of ovarian torsion. MRIs were retrospectively reviewed for presence of perifollicular T2 hypointense rim in the torsed ovary. Two arms of analysis were performed: (a) assessment of perifollicular hemorrhage on histological exam; and (b) assessment of ovarian viability after intra-operative detorsion. Sensitivity, specificity, positive predictive value, and negative predictive value of MRI for predicting ovarian viability in the setting of torsion was performed. κ test assessed level of agreement between readers. RESULTS 24 patients included in one of the two arms; 20 in viability analysis and 12 in perifollicular hemorrhage analysis (8 in both). The presence of T2-hypointense rim on MRI demonstrated 88.9% sensitivity and 66.7% specificity for the diagnosis of perifollicular hemorrhage on histology, and 91.7% sensitivity and 100% specificity for predicting intraoperative viability. CONCLUSION The presence of a perifollicular T2 hypointense rim on MRI in the setting of ovarian torsion correlates with perifollicular hemorrhage on histopathologic exam, and may also be a useful predictor of ovarian viability in patients presenting with ovarian torsion.

A Handheld Computer as Part of a Portable In Vivo Knee Joint Load-Monitoring System

In vivo measurement of loads and pressures acting on articular cartilage in the knee joint during various activities and rehabilitative therapies following focal defect repair will provide a means of designing activities that encourage faster and more complete healing of focal defects.It was the goal of this study to develop a totally portable monitoring system that could be used during various activities and allow continuous monitoring of forces acting on the knee. In order to make the monitoring system portable, a handheld computer with custom software, a USB powered miniature wireless receiver and a battery-powered coil were developed to replace a currently used computer, AC powered bench top receiver and power supply.A Dell handheld running Windows Mobile operating system(OS) programmed using Labview was used to collect strain measurements. Measurements collected by the handheld based system connected to the miniature wireless receiver were compared with the measurements collected by a hardwired system and a computer based system during bench top testing and in vivo testing. The newly developed handheld based system had a maximum accuracy of 99% when compared to the computer based system.