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.

Background and objectiveThe 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.Study design/materials and methodsA drop of a diluted overnight culture of BL21-293 E. coli expressing luciferase was seeded between the nc-YSZ implant and the agar plate. This was followed by immediate irradiation with selected laser. After each laser treatment the nc-YSZ was removed, and cultures were incubated for 24 hours at 37 °C. The study examined continuous wave (CW) and pulsed wave (PW) modes of near-infrared (NIR) 810 nm laser wavelength with a power output ranging from 1 to 3 W. During irradiation, the temperature distribution of nc-YSZ surface was monitored using an infrared thermal camera. Relative luminescence unit (RLU) was used to evaluate the viability of bacteria after the NIR laser treatment.ResultsAnalysis of RLU suggests that the viability of E. coli biofilm formation was reduced with NIR laser treatment when compared to the control group (P < 0.01) and loss of viability depends on both laser fluence and operation mode (CW or PW). The results demonstrate that while CW laser reduces the biofilm formation more than PW laser with the same power, the higher surface temperature of the implant generated by CW laser limits its medical efficacy. In contrast, with the right parameters, PW laser produces a more moderate photothermal effect which can be equally effective at controlling bacterial growth.ConclusionsOur results show that E. coli biofilm formation across the thickness of the nc-YSZ implant can be disrupted using NIR laser treatment. The results of this in vitro study suggest that using nc-YSZ as a cranial implant in vivo may also allow for locally selective, non-invasive, chronic treatment of bacterial layers (fouling) that might form under cranial implants, without causing adverse thermal damage to the underlying host tissue when appropriate laser parameters are used. Lasers Surg. Med. 48:782-789, 2016. © 2016 Wiley Periodicals, Inc

Transparent nanocrystalline yttria-stabilized-zirconia calvarium prosthesis

UnlabelledLaser-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.From the clinical editorIn 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

Windows to the Brain (WttB): Transparent Nanocrystalline Yttria Stabilized Zirconia Cranial Implants for Non-Invasive, Chronic Access to the Brain for Optical Diagnostics and Therapeutics

Windows to the Brain (WttB) platform can improve patient care by enabling the 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 facilitating diagnosis and treatment of a wide variety of brain pathologies and neurological disorders including cerebral edema, traumatic brain injury, stroke, glioma, and neurodegenerative diseases.We have developed a novel transparent nanocrystalline yttria-stabilized-zirconia (nc-YSZ) cranial implant (“window”) that can be used for laser and optogenetic therapy. Since light can be easily transmitted through it without undergoing excessive attenuation—the main obstacle for optical therapy and diagnostics of deep targets—this material was selected as an excellent candidate. To evaluate the potential of nc-YSZ cranial implants for optical therapy and imaging of the brain, we (1) demonstrated increased photon density in the brain of mice qualitatively and quantitatively with WttB in comparison to native skull using optical coherence tomography; (2) developed drug delivery techniques including micro-needling and application of pneumatic pressure to improve the drug perfusion of optical clearing agents to ex-vivo porcine skin; (3) confirmed the in vivo biocompatibility of nc-YSZ using a dorsal window chamber model; (4) evaluated the bactericidal effect of lasers by imaging of bioluminescent E. coli under WttB

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

Background and objectiveOptical 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.Study design/materials and methodsPropylene glycol (PG) OCA, either at room-temperature or heated to 45°C, was topically applied to hydrated, body temperature ex vivo porcine skin, in conjunction with various combinations of microneedling pre-treatment (0.2 mm length microneedles, performed prior to OCA application), vacuum pre-treatment (17-50 kPa, performed prior to OCA application), and positive pressure post-treatment (35-172 kPa, performed after OCA application). The effectiveness of OCA perfusion was characterized via measurements of transmittance, reduced scattering coefficient, and penetration depth at a number of medically-relevant laser wavelengths across the visible spectrum.ResultsTopical application of room-temperature (RT) PG led to an increase in transmittance across the visible spectrum of up to 21% relative to untreated skin. However, only modest increases were observed with addition of various combinations of microneedling pre-treatment, vacuum pre-treatment, and positive pressure post-treatment. Conversely, when heated PG was used in conjunction with these techniques, we observed significant increases in transmittance. Using an optimal PG perfusion enhancement protocol consisting of 45°C heated PG + microneedle pre-treatment + 35 kPa vacuum pre-treatment + 103 kPa positive pressure post-treatment, we observed up to 68% increase in transmittance relative to untreated skin, and up to 46% increase relative to topical RT PG application alone. Using the optimal PG perfusion enhancement protocol, we also observed up to 30% decrease in reduced scattering coefficient relative to untreated skin, and up to 20% decrease relative to topical RT PG alone. Finally, using the optimal protocol, we observed up to 25% increase in penetration depth relative to untreated skin, and up to 23% increase relative to topical RT PG alone.ConclusionsThe combination of heated PG, microneedling pre-treatment, vacuum pre-treatment, and positive pressure-post treatment were observed to significantly enhance the perfusion of topically applied PG. Although further studies are required to evaluate the efficacy of combined perfusion enhancement techniques in vivo, the current results suggest promise for facilitating the translation of OCAs to the clinic

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

Background and objectiveThe 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.Study design/materials and methodsA drop of a diluted overnight culture of BL21-293 E. coli expressing luciferase was seeded between the nc-YSZ implant and the agar plate. This was followed by immediate irradiation with selected laser. After each laser treatment the nc-YSZ was removed, and cultures were incubated for 24 hours at 37 °C. The study examined continuous wave (CW) and pulsed wave (PW) modes of near-infrared (NIR) 810 nm laser wavelength with a power output ranging from 1 to 3 W. During irradiation, the temperature distribution of nc-YSZ surface was monitored using an infrared thermal camera. Relative luminescence unit (RLU) was used to evaluate the viability of bacteria after the NIR laser treatment.ResultsAnalysis of RLU suggests that the viability of E. coli biofilm formation was reduced with NIR laser treatment when compared to the control group (P < 0.01) and loss of viability depends on both laser fluence and operation mode (CW or PW). The results demonstrate that while CW laser reduces the biofilm formation more than PW laser with the same power, the higher surface temperature of the implant generated by CW laser limits its medical efficacy. In contrast, with the right parameters, PW laser produces a more moderate photothermal effect which can be equally effective at controlling bacterial growth.ConclusionsOur results show that E. coli biofilm formation across the thickness of the nc-YSZ implant can be disrupted using NIR laser treatment. The results of this in vitro study suggest that using nc-YSZ as a cranial implant in vivo may also allow for locally selective, non-invasive, chronic treatment of bacterial layers (fouling) that might form under cranial implants, without causing adverse thermal damage to the underlying host tissue when appropriate laser parameters are used. Lasers Surg. Med. 48:782-789, 2016. © 2016 Wiley Periodicals, Inc

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

Transparent nanocrystalline yttria-stabilized-zirconia calvarium prosthesis.

UnlabelledLaser-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.From the clinical editorIn 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