Elastic moduli of tissues and synthetic polymeric materials are important design properties needed to develop new implants. In this paper we report the use of vibrational optical coherence tomography (VOCT) to measure the resonant frequency and calculate the modulus of tissues and synthetic polymers non-invasively and non-destructively in vitro and in vivo.Values of tissue and polymer moduli were obtained by applying an audible sinusoidal sound wave to the surface of each specimen. The sound wave travels to the interior of the material and is reflected back to the surface from underlying layers. A spectrum of resonant frequencies and moduli are then obtained. By analyzing the frequencies at which the maximum displacements are observed the resonant frequencies are determined of the material components and the moduli can then be calculated from calibration equations. The characteristic spectrum of resonant frequencies measured is a finger print by which the composition of the underlying tissue components can be determined using VOCT. The resonant frequencies of cells and tissues range from about 40 Hz for fat to about 990 Hz for

Early detection of skin cancer is of critical importance to provide five year survival rates that approach 99%. By 2050, one out of five Americans by age 70 will develop some form of skin cancer. This will result in a projected rate of 50 million skin biopsies per year given the current rate of escalation. In addition, the ability to differentiate between pigmented lesions and melanomas has proven a diagnostic challenge. While dermoscopy and visual analysis are useful in identifying many skin lesions, additional non-invasive techniques are needed to assist in the analysis of difficult to diagnose skin tumors. To augment dermoscopy data, we have developed 3D maps based on physical biomarker characteristics of benign and cancerous lesions using vibrational optical coherence tomography (VOCT). 3D images based on quantitative physical data involving changes in cellular and fibrous tissue stiffness along with changes in vascular quality are used to map and evaluate different types of cancers. 3D tumor maps constructed using quantitative VOCT data and OCT images have been used to characterize the differences between melanoma and other lesions. These characteristics can be used to plan the excision of difficult lesions where extensive surgery may be needed to remove the entire tumor in one step. In addition, it is now possible to use dermoscopy and VOCT to non-invasively differentiate between different cancerous lesion types using measurements of the resonant frequency of new cellular and vascular peaks. Quantitative VOCT information along with dermoscopic findings can be collected and analyzed remotely using artificial intelligence to improve cancerous tissue diagnosis.

Early detection of skin cancer is of critical importance since the five-year survival rate for early detected skin malignancies is 99% but drops to 27% for cancer that has spread to distant lymph nodes and other organs. Over 2.5 million benign skin biopsies (55% of the total) are performed each year in the US at an alarming cost of USD ~2.5 B. Therefore there is an unmet need for novel non-invasive diagnostic approaches to better differentiate between cancerous and non-cancerous lesions, especially in cases when there is a legitimate doubt that a biopsy may be required. The purpose of this study is to determine whether the differences in the extracellular matrices among normal skin, actinic keratosis (AK), basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) can be assessed non-invasively using vibrational optical coherence tomography (VOCT). VOCT is a new diagnostic technology that uses infrared light and audible sound applied transversely to tissue to measure the resonant frequencies and elastic moduli of cells, dermal collagen, blood vessels and fibrous tissue in skin and lesion stroma without physically touching the skin. Our results indicate that the cellular, vascular and fibrotic resonant frequency peaks are altered in AK, BCC and SCC compared to those peaks observed in normal skin and can serve as physical biomarkers defining the differences between benign and cancerous skin lesions. The resonant frequency is increased from a value of 50 Hz in normal skin to a value of about 80 Hz in pre- and cancerous lesions. A new vascular peak is seen at 130 Hz in cancerous lesions that may reflect the formation of new tumor blood vessels. The peak at 260 Hz is similar to that seen in the skin of a subject with Scleroderma and skin wounds that have healed. The peak at 260 Hz appears to be associated with the deposition of large amounts of stiff fibrous collagen in the stroma surrounding cancerous lesions. Based on the results of this pilot study, VOCT can be used to non-invasively identify physical biomarkers that can help differentiate between benign and cancerous skin lesions. The appearance of new stiff cellular, fragile new vessels, and stiff fibrous material based on resonant frequency peaks and changes in the extracellular matrix can be used as a fingerprint of pre- and cancerous skin lesions.

Background The modulus and resonant frequency of cancer cells and extracellular matrix are increased in both basal cell and squamous cell carcinomas, and in addition, the collagen stiffness is increased. The organization of the extracellular matrix surrounding cancer cells is clearly different than the extracellular matrix that is seen in normal skin. Materials and Methods We have used vibrational optical coherence tomography (VOCT) to measure the resonant frequency and stiffness of collagen, vascular, and reorganized fibrous extracellular matrix components. Measurements of vessels and fibrotic collagen content made on basal cell carcinomas (BCCs) are compared to similar measurements made on normal skin from different anatomical locations. Results Lesions with basal cell carcinomas exhibit characteristic resonant frequencies and moduli of reorganized extracellular matrix characteristic of fibrotic tissue. Cancerous lesions are characterized by dermal collagen (100 Hz), vascular (150 Hz), and fibrotic peaks (200‐230 Hz). The fibrotic peak is not found in areas of normal skin. Conclusions Based on this pilot study, it is hypothesized inflammation may promote precancerous lesion formation in the surrounding extracellular matrix. Measurement of the increases in vaculature and fibrotic content may be useful in early detection of BCCs.

Collagen and proteoglycans work in unison in the ECM to bear loads, store elastic energy and then dissipate excess energy to avoid tissue fatigue and premature mechanical failure. While collagen fibers store elastic energy by stretching the flexible regions in the triple helix, they do so by lowering their free energy through a reduction in the entropy and a decrease in charge–charge repulsion. Entropic increases occur when the load is released that drive the reversibility of the process and transmission of excess energy. Energy is dissipated by sliding of collagen fibrils by each other with the aid of decorin molecules that reside on the d and e bands of the native D repeat pattern. Fluid flow from the hydration layer associated with the decorin and collagen fibrils hydraulically dissipates energy during sliding. The deformation is reversed by osmotic forces that cause fluid to reform a hydration shell around the collagen fibrils when the loads are removed. In this paper a model is presented describing the organization of collagen fibers in the skin and cell–collagen mechanical relationships that exist based on non-invasive measurements made using vibrational optical coherence tomography. It is proposed that under external stress, collagen fibers form a tensional network in the plane of the skin. Collagen fiber tension along with forces generated by fibroblasts exerted on collagen fibers lead to an elastic modulus that is almost uniform throughout the plane of the skin. Tensile forces acting on cells and tissues may provide a baseline for stimulation of normal mechanotransduction. We hypothesize that during aging, changes in cellular metabolism, cell–collagen interactions and light and UV light exposure cause down regulation of mechanotransduction and tissue metabolism leading to tissue atrophy.

Energy storage and dissipation by composite materials are important design parameters for sensors and other devices. While polymeric materials can reversibly store energy by decreased chain randomness (entropic loss) they fail to be able to dissipate energy effectively and ultimately fail due to fatigue and molecular chain breakage. In contrast, composite tissues, such as muscle and tendon complexes, store and dissipate energy through entropic changes in collagen (energy storage) and viscous losses (energy dissipation) by muscle fibers or through fluid flow of the interfibrillar matrix. In this paper we review the molecular basis for energy storage and dissipation by natural composite materials in an effort to aid in the development of improved substrates for sensors, implants and other commercial devices. In addition, we introduce vibrational optical coherence tomography, a new technique that can be used to follow energy storage and dissipation by composite materials without physically touching them.

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