Christian Doppler Laboratory for Ocular and Dermal Effects of Thiomers

The present CD laboratory is focused towards the development of modified biopolymers for ocular and dermal use. Biopolymers are attractive for ocular applications due to their excellent safety profile with minimal toxicity. Molecules like hyaluronic acid (HA) or chitosan have been extensively studied in research both in the fields of ophthalmology and dermatology. Hyaluronic acid, for example, is used since many years as a lubricant substance for wetting the ocular surface in patients with dry eye disease (DED). In addition, due to its high biocompatibility and its common presence in the extracellular matrix of tissues, it gained popularity as a biomaterial scaffold in tissue engineering. Similarly, chitosan, a cationic biodegradable biopolymer, has drawn attention for ocular drug delivery based on its mucoadhesivity. It offers a permeation-enhancement for delivering materials across the cell surface, especially on mucosal surfaces.

Thiolated polymers (Thiomers) are mucoadhesive polymers which display thiol bearing side chains. With these modifications, the polymers exhibit new physical properties including improved mucoadhesion. In ocular applications thiolated chitosan might therefore overcome the general problem of all lubricants, which are characterized by a relatively short residence time on the ocular surface. In addition, due to the thiol groups, thiomers have more reactivity and enhanced protection against oxidation. Furthermore, there have been described properties related to permeation enhancement, in situ gelation and efflux inhibition.

The research within the CD laboratory is performed in cooperation with two industrial partners - Croma-Pharma, an Austrian family-owned company based in Leobendorf and Carl Zeiss Meditec located in Dublin, California. While the research with Croma Pharma is directed towards the pharmacological aspects and applicability of thiomers, Carl Zeiss Meditec’s main objective is the medical imaging of the eye for improved characterization of DED.

Therefore, two major topics are addressed in the scope of the Christian Doppler:

Qualitative and quantitative assessment of the precorneal tear film, tear meniscus and tear film lipid layer using ultrahigh-resolution (UHR)-OCT
Thiomers in the treatment of DED and in ocular and dermal woud healing

Figure 1. Exemplary cross-sectional images of murine skin obtained by (b) OCT and (c) HFUS and corresponding (a) histology (H&E staining). Enlarged cross-sections as indicated by the red rectangles are depicted in (d) and (e). Dashed yellow lines in image (a), (d) and (e) indicate the skin layers corresponding to: a) epidermis, b) papillary dermis, c) reticular dermis, d) subcutis, e) sebaceous glands and hair follicles, f) muscle. Skin layers with letters labeled with an asterisk are not distinguishable.

Schuetzenberger K, Pfister M, Messner A, Froehlich V, Garhoefer G, Hohenadl C, Schmetterer L, Werkmeister RM, “Comparison of optical coherence tomography and high frequency ultrasound imaging in mice for the assessment of skin morphology and intradermal volumes”, Scientific Reports, Volume 9, Issue 1 (September 2019), doi: 10.1038/s41598-019-50104-4

Figure 2. Image of the vasculature in the ear of a C57BL/6 mouse acquired via OCT angiography acquired with a custom-built OCT prototype based on an akinetic swept laser at ∼ 1310 nm with a bandwidth of 87 nm, providing an axial resolution of ∼ 6.5 µm in tissue.

Figure 3. Sample measurement of the human cornea using ultrahigh-resolution OCT. TF, tear film; EP, corneal epithelium; BL, Bowman’s layer; ST, corneal stroma; DM, Decement’s membrane; ED, corneal endothelium.

Werkmeister RM, Alex A, Kaya S, Unterhuber A, Hofer B, Riedl J, Bronhagl M, Vietauer M, Schmidl D, Schmoll T, Garhöfer G, Drexler W, Leitgeb RA, Groeschl M, Schmetterer L., “Measurement of tear film thickness using ultra-high resolution optical coherence tomography”, Invest Ophthalmol Vis Sci, Vol. 54, Issue 8 (August 2013), doi: 10.1167/iovs.13-11920.

Figure 4. In vivo measurements of the raw en face OCT reﬂectance of the air-tear interface obtained from the front surface of the central cornea in four healthy subjects (4 × 4 mm2) allows visualization of the tear film lipid layer,which has a thickness below 150 nm, far below the OCT axial resolution value of 1.2 µm.

Aranha Dos Santos V, Schmetterer L, Triggs GJ, Leitgeb RA, Gröschl M, Messner A, Schmidl D, Garhofer G, Aschinger GC, Werkmeister RM, „Super-resolved thickness maps of thin film phantoms and in vivo visualization of tear film lipid layer using OCT”, Biomed Opt Exp, Vol 7, Issue 7 (June 2016), doi: 10.1364/BOE.7.002650.

Figure 5. Automatic segmentation of the lower tear meniscus in a healthy subject. Exemplary image with light camera saturation in the center region. Calculated parameters (represented in yellow) are (A) tear meniscus area, (B) height, (C) depth and (D) radius of curvature. Green crosses represent the points used for the estimation of the radius of curvature.

Stegmann H, Aranha dos Santos V, Messner A, Unterhuber A, Schmidl D, Garhoefer G, Schmetterer L, and Werkmeister RM, “Automatic assessment of tear film and tear meniscus parameters in healthy subjects using ultrahigh-resolution optical coherence tomography”, Biomed Opt Express, Volume 10, Issue 6 (May 2019), doi: 10.1364/BOE.10.002744