Design for a low-cost heterodyne frequency domain-diffuse optical spectroscopy system.

A design for a low-cost, heterodyne, frequency domain-diffuse optical spectroscopy system is presented and validated. The system uses a single wavelength of 785 nm and a single detector to illustrate the capability, but is built in a modular fashion to make it easily expandable to additional wavelengths and detectors. The design incorporates methods to allow software-based control over the system operating frequency, laser diode output amplitude, and detector gain. Validation methods include characterization of electrical designs as well as determination of the system stability and accuracy using tissue-mimicking optical phantoms. The system requires only basic equipment for its construction and can be built for under $600.

Co-registered speckle contrast optical tomography and frequency domain-diffuse optical tomography for imaging of the fifth metatarsal.

A co-registered speckle contrast optical tomography and frequency domain-diffuse optical tomography system has been designed for imaging total hemoglobin concentration, blood oxygenation, and blood flow with the future aim of monitoring Jones fractures of the fifth metatarsal. Experimental validation was performed using both in vitro tissue-mimicking phantoms and in vivo cuff occlusion experiments. Results of these tissue phantom experiments ensure accurate recovery of three-dimensional distributions of optical properties and flow. Finally, cuff occlusion experiments performed on one healthy human subject demonstrate the system's ability to recover both decreasing tissue oxygenation and blood flow as caused by an arterial occlusion.

Towards detection of brain injury using multimodal non-invasive neuromonitoring in adults undergoing extracorporeal membrane oxygenation.

Extracorporeal membrane oxygenation (ECMO) is a form of cardiopulmonary bypass that provides life-saving support to critically ill patients whose illness is progressing despite maximal conventional support. Use in adults is expanding, however neurological injuries are common. Currently, the existing brain imaging tools are a snapshot in time and require high-risk patient transport. Here we assess the feasibility of measuring diffuse correlation spectroscopy, transcranial Doppler ultrasound, electroencephalography, and auditory brainstem responses at the bedside, and developing a cerebral autoregulation metric. We report preliminary results from two patients, demonstrating feasibility and laying the foundation for future studies monitoring neurological health during ECMO.

Investigating the effect of fatigue on muscle microvasculature blood flow during intermittent isometric contraction.

Localized muscle fatigue (LMF) decreases muscular strength, while affects the performance and potentially increases the risk of musculoskeletal disorders (MSD). An important mechanism in recovering from muscle fatigue is blood flow (BF). The BF response to muscle contraction and fatigue is highly dynamic and difficult to predict, as it depends on both metabolic demand and intramuscular pressure. The aim of this study was to measure both fatigue and BF during intermittent exertion of the first dorsal interosseous (FDI) muscle, in order to better characterize the relationship between BF and LMF during muscle contraction and rest. This study utilized Diffuse Correlation Spectroscopy (DCS) for BF measurement within the microvasculature of the FDI muscle. Exertion levels (EL) for intermittent fatiguing contraction were set to 20%, 30%, and 40% of an individual's maximum voluntary contraction (MVC). Our results showed that as an individual fatigued, relative BF rates increased, on average, by ~66% during exertion periods and ~330% during rest periods. Differences between exerting and resting BF increased over time for every EL (p<0.04), increasing by up to 11 times the baseline BF. At the same levels of muscle capacity (%MVC), resting BF was also found to increase with EL consistently. Our findings highlight BF dependence on both EL and history of muscle contraction. These results imply a variable recovery rate based on both the current state of contraction, (i.e., exertion vs. rest), and the muscle contraction history. The outcome of our study may facilitate the estimation of BF, thus, the muscle recovery rate, which can be implemented in the fatigue models to improve the prediction of muscle capacity to generate force/power.

Longitudinal 3D Blood Flow Distribution Provided by Diffuse Correlation Tomography during Bone Healing in a Murine Fracture Model.

Noninvasive monitoring of vascularization can potentially diagnose impaired bone healing earlier than current radiographic methods. In this study, a noncontact diffuse correlation tomography (DCT) technique was employed to measure longitudinal blood flow changes during bone healing in a murine femoral fracture model. The three-dimensional distribution of the relative blood flow was quantified from one day pre-fracture to 48 days post-fracture. For three mice, frequent DCT measurements were performed every other day for one week after fracture, and then weekly thereafter. A decrease in blood flow was observed in the bone fracture region at one day post-fracture, followed by a monotonic increase in blood flow beyond the pre-injury baseline until five to seven days post-fracture. For the remaining 12 mice, only weekly DCT measurements were performed. Data collected on a weekly basis show the blood flow for most mice was elevated above baseline during the first two post-fracture weeks, followed by a subsequent decrease. Torsional strength of the excised femurs was measured for all 15 mice after 7 weeks of healing. A metric based on the early blood flow changes shows a statistically significant difference between the high strength group and the low strength group.

Second-harmonic generation directionality is associated with neoadjuvant chemotherapy response in breast cancer core needle biopsies.

Neoadjuvant chemotherapy (NACT) is routinely administered to subsets of breast cancer patients, including triple negative (TN) or human epidermal growth factor receptor 2-positive (HER2+) cancers. After NACT and subsequent surgical resection, 5% to 30% of patients have no residual invasive carcinoma, termed pathological complete response. Unfortunately, many patients experience little-to-no response after NACT and unnecessarily suffer its side effects. Methods are needed to predict an individual patient's response to NACT. Core needle biopsies, taken before NACT, consist of tumor cells and the surrounding extracellular matrix. We performed second-harmonic generation (SHG) imaging of fibrillar collagen in core needle biopsy sections as a possible predictor of response to NACT. The ratio of forward-to-backward scattering (F/B) SHG was assessed in the "tumor bulk" and "tumor­host interface" in HER2+ and TN core needle biopsy sections. Patient response was classified post-treatment using the Residual Cancer Burden (RCB) score. In HER2+ biopsies, RCB class was associated with F/B derived from the tumor­stromal interface, but not tumor bulk. F/B was not associated with RCB class in TN biopsies. These findings suggest that F/B from needle biopsy sections may be a useful predictor of which patients will respond favorably to NACT, with the potential to help reduce overtreatment.

Non-invasive acoustic fabrication methods to enhance collagen hydrogel bioactivity.

Much attention has focused recently on utilizing components of the extracellular matrix (ECM) as natural building blocks for a variety of tissue engineering applications and regenerative medicine therapies. Consequently, new fabrication methods are being sought to enable molecular control over the structural characteristics of ECM molecules in order to improve their biological function. Exposing soluble collagen to acoustic forces associated with ultrasound propagation produces localized variations in collagen microfiber organization that in turn, promote cell behaviors essential for tissue regeneration, including cell migration and matrix remodeling. In the present study, mechanisms by which ultrasound interacts with polymerizing collagen to produce functional changes in collagen microstructure were investigated. The rate of collagen polymerization was manipulated by adjusting the pH of collagen solutions and the temperature at which gels were polymerized. Results demonstrate that the phase transition of type I collagen from fluid to gel triggered a simultaneous increase in acoustic absorption. This phase transition of collagen involves the lateral growth of early-stage collagen microfibrils and importantly, corresponded to a defined period of time during which exposure to ultrasound introduced both structural and functional changes to the resultant collagen hydrogels. Together, these experiments isolated a critical window in the collagen fiber assembly process during which mechanical forces associated with ultrasound propagation are effective in producing structural changes that underlie the ability of acoustically-modified collagen hydrogels to stimulate cell migration. These results demonstrate that changes in material properties associated with collagen polymerization are a fundamental component of the mechanism by which acoustic forces modify collagen biomaterials to enhance biological function.