Final efficacy and cost analysis of a fish skin graft vs standard of care in the management of chronic diabetic foot ulcers: a prospective, multicenter, randomized controlled clinical trial.

INTRODUCTION: DFUs remain a cause of significant morbidity. OBJECTIVE: This is the third of 3 planned articles reporting on a prospective, multicenter, randomized controlled trial evaluating the use of omega-3-rich acellular FSG compared with CAT in the management of DFUs. MATERIALS AND METHODS: A total of 102 patients with a DFU (n = 51 FSG, n = 51 CAT) participated in the trial as ITT candidates, with 77 of those patients included in the PP analysis (n = 43 FSG, n = 34 CAT). Six months after treatment, patients with healed ulcers were followed up for ulcer recurrence. A cost analysis model was applied in both treatment groups. RESULTS: The proportion of closed wounds at 12 weeks was compared, as were the secondary outcomes of healing rate and mean PAR. Diabetic foot wounds treated with FSG were significantly more likely to achieve closure than those managed with CAT (ITT: 56.9% vs 31.4%; P =.0163). The mean PAR at 12 weeks was 86.3% for FSG vs 64.0% for CAT (P =.0282). CONCLUSIONS: Treatment of DFUs with FSG resulted in significantly more wounds healed and an annualized cost savings of $2818 compared with CAT.

Mueller matrix polarimetry and polar decomposition of articular cartilage imaged in reflectance.

Articular cartilage birefringence relates to zonal architecture primarily of type II collagen, which has been assessed extensively in transmission, through thin tissue sections, to evaluate cartilage repair and degeneration. Mueller matrix imaging of articular cartilage in reflection is of potential utility for non-destructive imaging in clinical and research applications. Therefore, such an imaging system was constructed to measure laser reflectance signals, calibrated, and tested with optical standards. Polar decomposition was chosen as a method to extract fundamental optical parameters from the experimental Mueller matrices, with performance confirmed by simulations. Adult bovine articular cartilage from the patellofemoral groove was found to have ∼0.93 radians retardance, low diattenuation of ∼0.2, and moderately high depolarization of 0.66. Simulations showed that variation in depolarization drives inaccuracy of depolarization and retardance maps derived by polar decomposition. These results create a basis for further investigation of the clinical utility of polarized signals from knee tissue and suggest potential approaches for improving the accuracy of polar decomposition maps.

Pulsed focused ultrasound lowers interstitial fluid pressure and increases nanoparticle delivery and penetration in head and neck squamous cell carcinoma xenograft tumors.

Nanocarriers offer a promising approach to significantly improve therapeutic delivery to solid tumors as well as limit the side effects associated with anti-cancer agents. However, their relatively large size can negatively affect their ability to efficiently penetrate into more interior tumor regions, ultimately reducing therapeutic efficacy. Poor penetration of large agents such as nanocarriers is attributed to factors in the tumor microenvironment such as elevated interstitial fluid pressure (IFP) and fibrillar collagen in the extracellular matrix. Our previous studies reported that pretreatment of solid tumor xenografts with nondestructive pulsed focused ultrasound (pFUS) can improve the delivery and subsequent therapy of a variety of therapeutic formulations in different tumor models, where the results were associated with expanded extracellular spaces (ECS), an increase in hydraulic conductivity, and decrease in tissue stiffness. Here, we demonstrate the inverse relationship between IFP and the penetration of systemically administered nanoparticle (NP) probes, where IFP increased from the tumor periphery to their center. Furthermore, we show that pretreatment with pFUS can safely reduce IFP and improve NP delivery; especially into the center of the tumors. These results coincide with effects generated in the fibrillar collagen network microstructure in the ECS as determined by quantitative polarized light microscopy. Whole tumor and histomorphometric analysis, however, did not show significant differences in collagen area fraction or collagen feature solidity, as well as tumor cross-sectional area and aspect ratio, as a result of the treatments. We present a biophysical model connecting the experimental results, where pFUS-mediated cytoarchitectural changes are associated with improved redistribution of the interstitial fluid and lower IFP. The resulting improvement in NP delivery supports our previous therapeutic studies and may have implications for clinical applications to improve therapeutic outcomes in cancer therapy.

Microstructural densification and alignment by aspiration-ejection influence cancer cell interactions with three-dimensional collagen networks.

Extracellular matrix microstructure and mechanics are crucial to breast cancer progression and invasion into surrounding tissues. The peritumor collagen network is often dense and aligned, features which in vitro models lack. Aspiration of collagen hydrogels led to densification and alignment of microstructure surrounding embedded cancer cells. Two metastasis-derived breast cancer cell lines, MDA-MB-231 and MCF-7, were cultured in initially 4 mg/ml collagen gels for 3 days after aspiration, as well as in unaspirated control hydrogels. Videomicroscopy during aspiration, and at 0, 1, and 3 days after aspiration, epifluorescence microscopy of phalloidin-stained F-actin cytoskeleton, histological sections, and soluble metabolic byproducts from constructs were collected to characterize effects on the embedded cell morphology, the collagen network microstructure, and proliferation. Breast cancer cells remained viable after aspiration-ejection, proliferating slightly less than in unaspirated gels. Furthermore, MDA-MB-231 cells appear to partially relax the collagen network and lose alignment 3 days after aspiration. Aspiration-ejection generated aligned, compact collagen network microstructure with immediate cell co-orientation and higher cell number density apparently through purely physical means, though cell-collagen contact guidance and network remodeling influence cell organization and collagen network microstructure during subsequent culture. This study establishes a platform to determine the effects of collagen density and alignment on cancer cell behavior, with translational potential for anticancer drug screening in a biomimetic three-dimensional matrix microenvironment, or implantation in preclinical models.

Noninvasive assessment of articular cartilage surface damage using reflected polarized light microscopy.

Articular surface damage occurs to cartilage during normal aging, osteoarthritis, and in trauma. A noninvasive assessment of cartilage microstructural alterations is useful for studies involving cartilage explants. This study evaluates polarized reflectance microscopy as a tool to assess surface damage to cartilage explants caused by mechanical scraping and enzymatic degradation. Adult bovine articular cartilage explants were scraped, incubated in collagenase, or underwent scrape and collagenase treatments. In an additional experiment, cartilage explants were subject to scrapes at graduated levels of severity. Polarized reflectance parameters were compared with India ink surface staining, features of histological sections, changes in explant wet weight and thickness, and chondrocyte viability. The polarized reflectance signal was sensitive to surface scrape damage and revealed individual scrape features consistent with India ink marks. Following surface treatments, the reflectance contrast parameter was elevated and correlated with image area fraction of India ink. After extensive scraping, polarized reflectance contrast and chondrocyte viability were lower than that from untreated explants. As part of this work, a mathematical model was developed and confirmed the trend in the reflectance signal due to changes in surface scattering and subsurface birefringence. These results demonstrate the effectiveness of polarized reflectance microscopy to sensitively assess surface microstructural alterations in articular cartilage explants.

Noninvasive surface damage assessment of bovine articular cartilage explants by reflected polarized light microscopy.

Articular surface damage is a hallmark of cartilage degeneration. Noninvasive assessment of cartilage microstructural alterations has potential clinical value. In this study, we use bovine patellofemoral articular cartilage explants treated with mechanical scraping and collagenase to create cartilage surface disruption, and use polarized reflectance microscopy to quantify alterations to surface and sub-surface microstructure. Reflected polarized signal was sensitive to mild damage to the cartilage surface, and highlighted disruptive alterations. The results indicate the efficacy of reflected polarized light microscopy in assessing the microstructural status of superficial articular cartilage.