Surgical probe and implant development for nucleus pulposus replacements

Intervertebral disc degeneration is a major reason why we experience low back pain. Intervertebral discs are located in-between the vertebrae of the spine. They act, among other, as shock absorbers by distributing the mechanical load applied to the spine while giving it its range of motion. An intervertebral disc is composed of a center - a soft core, called nucleus pulposus which is surrounded by a strong ring called the annulus fibrosus. By disc degeneration, we mean a physical deterioration of either the nucleus and/or the annulus. It has been posited that low back pain could be alleviated by replacing the degenerated nucleus pulposus by a synthetic implant. However, such nucleus pulposus replacements have been subjected to highly controversial discussions over the last 50 years and their use has not yet resulted in a positive outcome to treat degenerated disc disease. In this thesis, we report on the development of an implant material consisting of poly(ethylene glycol)dimetacrylate - a hydrogel - loaded with nano-fibrillated cellulose. Photopolymerization was selected as a polymerization method to "harden" the implant in situ. Thus, the implant can be injected in a liquid state through the annulus fiborsus with a small diameter cannula. Furthermore, an in situ photopolymerization method was developed along with an implanting device which was used to insert the composite hydrogel into an intervertebral disc ex vivo. The volume of a human nucleus pulposus is several 100 cubic millimeters, which is a substantial volume to photopolymerize. In order to ensure a homogeneous photopolymerization of this volume, a Monte Carlo model was developed. The model is able to predict accurately the volume of the photopolymerized implant in tissue cavities. This simulation tool was used to tailor the light scattering properties of the hydrogel by loading it with lipid particles. Thus, spherical implant shapes could be photopolymerized. An implanting device was developed to inject and photopolymerize the liquid implant while monitoring the cross-linking reaction of the implant during photopolymerization using fluorescence spectroscopy in situ and in real-time. Using this device, synthetic nucleus pulposus implants were successfully inserted through a 1 mm incision in the annulus fiborsus of an ex vivo bovine intervertebral disc model and the long-term performance of the proposed nucleus pulposus replacement was evaluated. The changes of the fluorescence signal throughout the photopolymerization reaction could be shown to correlate with the photopolymerization volume. It was thus possible to insert the synthetic implant in a controlled manner into the bovine disc model. The implant was able to significantly re-establish intervertebral disc height after surgery (p < 0.0025) and maintain it over 0.5 million loading cycles (p < 0.025). Disc height is one of the essential parameters to restore and maintain in an intervertebral disc. The excellent results achieved in these ex vivo experiments validated the implantation method and the device. More importantly, they showed that the novel implant material might resist mechanical loads similar to the loads that would be experienced in everyday life. However, longer tests (~ 10 million cycles) are required to determine whether this material would truly resists during a clinical study

Geometry- and load-specific optimization of the collagen network's fibre orientation in the lumbar spine's annulus fibrosus

In Europe, low back pain (LBP) affects the quality of life of up to 30% of the active population. Although the origin of LBP is not well identified and is probably not unique, epidemiological studies suggest that the severity of the disease is correlated with mechanical factors. The lumbar spine is a complex structure where bone, cartilage, ligaments, and muscles have specific and functional mechanical interactions that depend on the shape and structure of each tissue. Thus, any local tissue abnormality may generate non-physiological loadings on surrounding tissues, extending or catalysing a pre-existing degenerative process. To date, lumbar spine finite element modelling is one of the most promising methods to thoroughly investigate functional load transfers between the different spine tissues. However, many geometrical or mechanical parameters used for tissue modelling are still not quantified and need to be assumed. Previous computational studies demonstrated that the intervertebral disc (IVD) plays a key role in distributing the internal forces across the lumbar spine structure. Within the IVD, together with the nucleus pulposus (NP) pressure, the annulus fibrosus (AF) collagen organization is one of the most influential parameter for the disc stabilization. However, AF collagen organization is not unique and seems to depend on the particularity of spine morphologies. Therefore, any lumbar spine model based on particular geometrical data would require specific definitions of fibre-induced AF anisotropy. Unfortunately, particular AF anisotropies are hardly measurable. Thus, the present project aims to investigate the stabilization of a L4-L5 lumbar spine bi-segment finite element model as a function of the AF fibre orientations. For this, a mathematical function, based on local AF matrix shear strains, fibre stresses and fibre stress distribution has been proposed. In this function was implemented and was partially validated on smaller AF model. Enhancements could be proposed and be applied to the L4-L5 model. Methods and procedure to optimize annulus AF orientations could be validated. The proposed evaluation function had to be changed. It was found that an optimal orientation depends mainly on fibre stress and matrix shear stress. The optimizations converged to average angles between 32 and 68 and radial gradients between 10 and 17 degree. Tangential gradients could not be found. Moreover a critical fibre angle could be determined where fibre under uni-axial load are not loaded any more. Using literature data it was possible to solve one of the main issues of collagen fibre orientations in the AF and to bring together the two hypothesis of either a only radial or only a tangential gradient. Moreover it was concluded that pre-stress respectively hoop stress is an nonnegligible factor which has to be accounted for in IVD finite element models

Miniature probe for the delivery and monitoring of a photopolymerizable material

Photopolymerization is a common method to cure materials initially in a liquid state, such as dental implants or bone or tissue fillers. Recent advances in the development of biocompatible gel- and cement-systems open up an avenue for in situ photopolymerization. For minimally invasive surgery, such procedures require miniaturized surgical endoscopic probes to activate and control photopolymerization in situ. We present a miniaturized light probe in which a photoactive material can be (1) mixed, pressurized, and injected, (2) photopolymerized/photoactivated, and (3) monitored during the chemical reaction. The device is used to implant and cure poly(ethylene glycol) dimethacrylate-hydrogel-precursor in situ with ultraviolet A (UVA) light (365 nm) while the polymerization reaction is monitored in real time by collecting the fluorescence and Raman signals generated by the 532 nm excitation light source. Hydrogels could be delivered, photopolymerized, and monitored by the probe up to a curing depth of 4 cm. The size of the photopolymerized samples could be correlated to the fluorescent signal collected by the probe, and the reproducibility of the procedure could be demonstrated. The position of the probe tip inside a bovine caudal intervertebral disc could be estimated in vitro based on the collected fluores- cence and Raman signal

Photo-polymerization, swelling and mechanical properties of cellulose fibre reinforced poly(ethylene glycol) hydrogels

The application of hydrogels as load-bearing biomedical components is often limited by their mechanical properties. Often an attempt to improve a hydrogel's stiffness is accompanied by a loss of toughness and swelling properties. In this work, we show that the addition of nanofibrillated cellulose (NFC) provides a mean to tailor both the swelling and the mechanical properties of the hydrogel. Various volume fractions of NFC were added to poly(ethylene glycol) dimethacrylate (PEGDM) precursors with two different molecular weights (6 and 20 kDa). The viscosity measurements of the precursor solutions indicated that the dispersed NFCs form a network-like structure in the hydrogel precursor. Such a structure, as observed in the photo-rheology experiments, serves as a light-scattering source when the solution is illuminated by UV light, which provides a uniform polymerization of the hydrogel in three-dimension and reduces the curing time. Mechanical properties of the neat and composite hydrogels were characterized using monotonic and cyclic compression tests. NFC reinforcement increases the hydrogel's stiffness by a factor 2 and 3.5 for the PEGDM matrixes with molecular weights of 6 and 20 kDa respectively without compromising their toughness. Moreover, the desired stiffness and swelling properties can be simultaneously achieved by adapting the reinforcement concentration and the hydrogel cross-link density. The obtained composite hydrogels offer enhanced and tuneable properties and are proposed for injectable and photo-curable load-bearing implants

The SIB Swiss Institute of Bioinformatics' resources: focus on curated databases

The SIB Swiss Institute of Bioinformatics (www.isb-sib.ch) provides world-class bioinformatics databases, software tools, services and training to the international life science community in academia and industry. These solutions allow life scientists to turn the exponentially growing amount of data into knowledge. Here, we provide an overview of SIB's resources and competence areas, with a strong focus on curated databases and SIB's most popular and widely used resources. In particular, SIB's Bioinformatics resource portal ExPASy features over 150 resources, including UniProtKB/Swiss-Prot, ENZYME, PROSITE, neXtProt, STRING, UniCarbKB, SugarBindDB, SwissRegulon, EPD, arrayMap, Bgee, SWISS-MODEL Repository, OMA, OrthoDB and other databases, which are briefly described in this article

Curable filler material for tubular structures

A radiopaque composition with low viscosity and increased photopolymerizability for application or filling of hollow structures is disclosed. Moreover, a method to apply and monitor the application and/or the photopolymerization of the composition are presented

Device and method for injection, photoactivation and solidifaction of liquid embolic material in the vascular system or other organic cavities

The present invention concerns an organic cavity injection device including an injection cannula for injecting a photo-activatable substance inside an organic cavity; at least one element or a plurality of elements configured to control the removal of a resident substance from the organic cavity and simultaneously prevent removal of the non-activated photo-activatable substance from the organic cavity; and an optical waveguide for providing electromagnetic radiation inside the organic cavity to the photo-activatable substance to photoactive the photo- activatable substance inside the organic cavity