Guillermo Aguilar

Transparent Nanocrystalline Yttria-Stabilized-Zirconia Calvarium Prosthesis

UNLABELLEDnLaser-based diagnostics and therapeutics show promise for many neurological disorders. However, the poor transparency of cranial bone (calvaria) limits the spatial resolution and interaction depth that can be achieved, thus constraining opportunity in this regard. Herein, we report preliminary results from efforts seeking to address this limitation through use of novel transparent cranial implants made from nanocrystalline yttria-stabilized zirconia (nc-YSZ). Using optical coherence tomography (OCT) imaging of underlying brain in an acute murine model, we show that signal strength is improved when imaging through nc-YSZ implants relative to native cranium. As such, this provides initial evidence supporting the feasibility of nc-YSZ as a transparent cranial implant material. Furthermore, it represents a crucial first step towards realization of an innovative new concept we are developing, which seeks to eventually provide a clinically-viable means for optically accessing the brain, on-demand, over large areas, and on a chronically-recurring basis, without need for repeated craniectomies.nnnFROM THE CLINICAL EDITORnIn this study, transparent nanocrystalline yttria-stabilized-zirconia is used as an experimental cranium prosthesis material, enabling the replacement of segments of cranial bone with a material that allows for optical access to the brain on a recurrent basis using optical imaging methods such as OCT.

Waveguide-like structures written in transparent polycrystalline ceramics with an ultra-low fluence femtosecond laser

We present a laser processing study of optically transparent ytrria stabilized zirconia (YSZ) ceramics (ZrO2-8 mol. % Y2O3) using unamplified femtosecond (fs) laser pulses of a few nJ and high repetition rate (70 MHz). The ceramics were fabricated using current activated pressure assisted densification (CAPAD) and have fine grain size and minimal porosity, producing a transparent material. Irradiation using fs laser pulses caused permanent changes in the optical properties of the irradiated zone. These laser written structures were found to confine He-Ne laser light (632 nm) in effect functioning as waveguide like structures and were written into the YSZ ceramics using a remarkably low per-pulse energy (5nJ). The number of passes with the laser i.e total incident pulses per unit area was found to significantly affect the waveguide writing. We believe that waveguides are regions were the concentration of oxygen vacancies and/or their associated free electrons have been altered by laser irradiation. We are not aware of previous reports of low fluence fs laser pulses being used to influence vacancy related defects to produce waveguides in ceramics. This new mechanism opens the door for writing strictures in optical ceramics with lower power than previously thought feasible.

Inflammatory response to implantation of transparent nanocrystalline yttria-stabilized zirconia using a dorsal window chamber model

The long-range goal of the windows to the brain (WttB) is to improve patient care by providing a technique for delivery and/or collection of light into/from the brain, on demand, over large areas, and on a chronically-recurring basis without the need for repeated craniotomies. To evaluate the potential of nanocrystalline yttria-stabilized-zirconia (nc-YSZ) cranial implant for optical therapy and imaging, in vivo biocompatibility was studied using the dorsal window chamber model in comparison with control (no implant) and commercially available cranial implant materials (PEEK and PEKK). The host tissue response to implant was characterized by using transillumination and fluorescent microscopy to measure leukocyte adhesion, blood vessel diameter, blood flow rate, and vascular permeability over two weeks. The results indicated the lack of inflammatory reaction of the host tissue to nc-YSZ at the microscopic level, suggesting that nc-YSZ is a good alternative material for cranial implants.

Evaluation of laser bacterial anti-fouling of transparent nanocrystalline yttria-stabilized-zirconia cranial implant.

The development and feasibility of a novel nanocrystalline yttria‐stabilized‐zirconia (nc‐YSZ) cranial implant has been recently established. The purpose of what we now call “window to the brain (WttB)” implant (or platform), is to improve patient care by providing a technique for delivery and/or collection of light into/from the brain, on demand, over large areas, and on a chronically recurring basis without the need for repeated craniotomies. WttB holds the transformative potential for enhancing light‐based diagnosis and treatment of a wide variety of brain pathologies including cerebral edema, traumatic brain injury, stroke, glioma, and neurodegenerative diseases. However, bacterial adhesion to the cranial implant is the leading factor for biofilm formation (fouling), infection, and treatment failure. Escherichia coli (E. coli), in particular, is the most common isolate in gram‐negative bacillary meningitis after cranial surgery or trauma. The transparency of our WttB implant may provide a unique opportunity for non‐invasive treatment of bacterial infection under the implant using medical lasers.

Optical clearing agent perfusion enhancement via combination of microneedle poration, heating and pneumatic pressure.

Optical clearing agents (OCAs) have shown promise for increasing the penetration depth of biomedical lasers by temporarily decreasing optical scattering within the skin. However, their translation to the clinic has been constrained by lack of practical means for effectively perfusing OCA within target tissues in vivo. The objective of this study was to address this limitation through combination of a variety of techniques to enhance OCA perfusion, including heating of OCA, microneedling and/or application of pneumatic pressure over the skin surface being treated (vacuum and/or positive pressure). While some of these techniques have been explored by others independently, the current study represents the first to explore their use together.

Antibacterial studies of ZnO nanoparticle coatings on nanocrystalline YSZ irradiated with femtosecond laser light

Recently, efforts have been made to create a transparent ceramic cranial implant comprised of nanocrystalline yttriastabilized zirconia (nc-YSZ) that will provide optical access to the brain. This has been referred to as Window to the Brain (WttB) in the literature. WttB will allow the use of laser and photonic treatments and diagnostics in areas with difficult optical access in the brain. Nevertheless, infection is still one of the frequent cranial implant complications. In most cases a second surgery is required to replace the infected implant. To address potential infections in the WttB platform, we have studied the antibacterial effect of a Zinc Oxide (ZnO) nanoparticles coating on nc-YSZ. After coating with ZnO nanoparticles, the implant was irradiated with infrared femtosecond laser light. We synthesized ZnO nanoparticles through the Laser Ablation of Solids in Liquids (LASL) method, using a Zinc solid target in a liquid medium (water/acetone). Antibacterial coatings were obtained by air brush, using a precursor solution of ZnO nanoparticles in distilled water. Escherichia coli (E. coli) have been used as representative, clinical relevant bacteria to probe the antibacterial effect of the coating. Our previous studies suggested that the use of ZnO nanoparticles inhibit bacterial growth. Laser irradiation treatment alone also offers inhibition of bacterial growth, up to 70%. The incorporation of nanoparticles offers an additional 20% inhibition. Thus, this work represents the next step towards the development of a clinically-oriented transparent cranial implant.

Laser speckle imaging of brain blood flow through a transparent nanocrystalline yttria-stabilized-zirconia cranial implant

The laser speckle flowmetry methods based on laser speckle imaging (LSI) have attracted extensive attention recently because they can image brain blood flow with high spatiotemporal resolution. However, the poor transparency of the cranial bone limits the spatial resolution and the imaging depth. This problem has previously been addressed in animal studies by removing or thinning the skull to transparency. Nevertheless, a permanent and reliable solution has not yet been developed. Our study demonstrates a new method to address this challenge in biomedical imaging research, through the use of novel transparent cranial implants made from nanocrystalline yttria-stabilized zirconia (nc-YSZ). By applying LSI to underlying brain in an acute murine model, we show that spatial resolution and quantitative accuracy of blood flow measurement are improved when imaging through transparent nc-YSZ implants relative to native cranium. As such, these results provide the initial evidence supporting the feasibility of nc-YSZ transparent cranial implant as a clinically-viable long-term optical access for LSI on a chronically-recurring basis, thereby suppressing the need for repeated craniotomies. Successful development of this method has the potential to advance the study of neuropathologies or novel neuro-procedures in animal models where measurement of cerebral blood flow is of interest, such as blood flow changes during stroke, changes in blood flow due to functional activation, and spreading depolarization and its role in brain injuries, pathophysiology of migraine, and subarachnoid hemorrhage.

Laser-excited gold nanoparticles for treatment of cancer cells in vitro

Several in vitro and in vivo studies have been performed to investigate the potential of Photothermal Therapy (PTT) as a cancer treatment strategy. However, there are still open questions concerning the optimal parameters for generating cavitation bubbles and acoustic shockwaves for increasing the damage to malignant cells, and the primary mechanism for cell damage in PTT is still a matter of debate. This study investigates PTT based on shockwaves from cavitation induced far from the cells, due to laser absorption by gold nanorods (GNR) colloidal solutions in vitro. The effects of laser energy and distance from the cavitation on cell viability is investigated in PC3 prostate cancer cells, and Escherichia coli (E. coli) cells, respectively.

Femtosecond laser assisted antibacterial activity of ZnO nanoparticles

Bacterial infection of cranial implants remains a major cause of implant failure, and often requires surgical intervention to remove and replace the fouled implant. Novel transparent implants may allow for mitigation of infection using optical therapies, without the need for invasive surgeries. In this study, we investigate a combined treatment with ZnO nanoparticles and femtosecond laser pulses to inhibit the growth of Escherichia coli (E. Coli) in vitro. The combined effect has shown a substantial reduction in the number of CFU/mL after incubation compared with no treatment.

Novel Cranial Implants of Yttria-Stabilized Zirconia as Acoustic Windows for Ultrasonic Brain Therapy.

Therapeutic ultrasound can induce changes in tissues by means of thermal and nonthermal effects. It is proposed for treatment of some brain pathologies such as Alzheimers, Parkinsons, Huntingtons diseases, and cancer. However, cranium highly absorbs ultrasound reducing transmission efficiency. There are clinical applications of transcranial focused ultrasound and implantable ultrasound transducers proposed to address this problem. In this paper, biocompatible materials are proposed for replacing part of the cranium (cranial implants) based on low porosity polycrystalline 8 mol% yttria-stabilized-zirconia (8YSZ) ceramics as acoustic windows for brain therapy. In order to assess the viability of 8YSZ implants to effectively transmit ultrasound, various 8YSZ ceramics with different porosity are tested; their acoustic properties are measured; and the results are validated using finite element models simulating wave propagation to brain tissue through 8YSZ windows. The ultrasound attenuation is found to be linearly dependent on ceramics porosity. Results for the nearly pore-free case indicate that 8YSZ is highly effective in transmitting ultrasound, with overall maximum transmission efficiency of ≈81%, compared to near total absorption of cranial bone. These results suggest that 8YSZ polycrystals could be suitable acoustic windows for ultrasound brain therapy at 1 MHz.