Injectable hydrogel induces regeneration of naturally degenerate human intervertebral discs in a loaded organ culture model.

Low back pain resulting from disc degeneration is a leading cause of disability worldwide. However, to date few therapies target the cause and fail to repair the intervertebral disc (IVD). This study investigates the ability of an injectable hydrogel (NPgel), to inhibit catabolic protein expression and promote matrix expression in human nucleus pulposus (NP) cells within a tissue explant culture model isolated from degenerate discs. Furthermore, the injection capacity of NPgel into naturally degenerate whole human discs, effects on mechanical function, and resistance to extrusion during loading were investigated. Finally, the induction of potential regenerative effects in a physiologically loaded human organ culture system was investigated following injection of NPgel with or without bone marrow progenitor cells. Injection of NPgel into naturally degenerate human IVDs increased disc height and Young's modulus, and was retained during extrusion testing. Injection into cadaveric discs followed by culture under physiological loading increased MRI signal intensity, restored natural biomechanical properties and showed evidence of increased anabolism and decreased catabolism with tissue integration observed. These results provide essential proof of concept data supporting the use of NPgel as an injectable therapy for disc regeneration. STATEMENT OF SIGNIFICANCE: Low back pain resulting from disc degeneration is a leading cause of disability worldwide. However, to date few therapies target the cause and fail to repair the intervertebral disc. This study investigated the potential regenerative properties of an injectable hydrogel system (NPgel) within human tissue samples. To mimic the human in vivo conditions and the unique IVD niche, a dynamically loaded intact human disc culture system was utilised. NPgel improved the biomechanical properties, increased MRI intensity and decreased degree of degeneration. Furthermore, NPgel induced matrix production and decreased catabolic factors by the native cells of the disc. This manuscript provides evidence for the potential use of NPgel as a regenerative biomaterial for intervertebral disc degeneration

Social Relations and Relational Incentives

This paper studies how social relationships between managers and employees affect relational incentive contracts. To this end we develop a simple dynamic principal-agent model where both players may have feelings of altruism or spite toward each other. The contract may contain two types of incentives for the agent to work hard: a bonus and a threat of dismissal. We find that good social relationships undermine the credibility of a threat of dismissal but strengthen the credibility of a bonus. Among others, these two mechanisms imply that better social relationships sometimes lead to higher bonuses, while worse social relationships may increase productivity and players' utility in equilibrium

Cadaveric device-injected very high-viscosity cement during vertebroplasty

Introduction: Cement extravasation during vertebroplasty (VP) is the most commonly reported complication. Cement viscosity is considered the single most important predictor of the risk of extravasation. Certainly, injecting high-viscosity cement (HVC) is difficult to utilize in real practice. We invented a new device capable of injecting high-viscosity with ease and at a distance to avoid radiation. The aim of this study is to confirm the efficacy and safety of the new device on cadaveric vertebrae. Methodology: A 126 osteoporotic vertebral bodies were harvested from cadavers. Eighty vertebrae were included in the study. Computer-randomization software was used to allocate specimens over two main groups, Conventional VP and New Device. Both groups were further subdivided into two subgroups; high-viscosity and low-viscosity. A custom device was used on each vertebra to induce a compression fracture. Results: Injecting HVC was associated with a lower leakage volume compared with low-viscosity cement. HVC was associated with no leakage into the spinal canal. It was also associated with a low incidence of vascular extravasation (P < 0.001). The mean volume of cement leakage in the low-viscosity group was 0.23 and 0.15 cc, for the Conventional VP and New Device, respectively. In both groups, the most common site for leakage was the vertebral end plate, which was exhibited more in the low-viscosity group (71.5%) compared with the high-viscosity group (42.5%). The preset target amount of cement to be injected was reached in 99% of the time when injecting HVC with the New Device, compared with 62% using the Conventional VP. In both groups, there was no correlation between the amount of cement injected and the amount of leakage. Conclusion: The new device is capable of injecting HVC easily, with a lower incidence of cement leakage. It also minimized the risk of radiation exposure to the surgeon

Investigating Commercial Filaments for 3D Printing of Stiff and Elastic Constructs with Ligament-Like Mechanics

The current gold standard technique for treatment of anterior cruciate ligament (ACL) injury is reconstruction with autograft. These treatments have a relatively high failure and re-tear rate. To overcome this, tissue engineering and additive manufacturing are being used to explore the potential of 3D scaffolds as autograft substitutes. However, mechanically optimal polymers for this have yet to be identified. Here, we use 3D printing technology and various materials with the aim of fabricating constructs better matching the mechanical properties of the native ACL. A fused deposition modeling (FDM) 3D printer was used to microfabricate dog bone-shaped specimens from six different polymers&mdash;PLA, PETG, Lay FOMM 60, NinjaFlex, NinjaFlex-SemiFlex, and FlexiFil&mdash;at three different raster angles. The tensile mechanical properties of these polymers were determined from stress&ndash;strain curves. Our results indicate that no single material came close enough to successfully match reported mechanical properties of the native ACL. However, PLA and PETG had similar ultimate tensile strengths. Lay FOMM 60 displayed a percentage strain at failure similar to reported values for native ACL. Furthermore, raster angle had a significant impact on some mechanical properties for all of the materials except for FlexiFil. We therefore conclude that while none of these materials alone is optimal for mimicking ACL mechanical properties, there may be potential for creating a 3D-printed composite constructs to match ACL mechanical properties. Further investigations involving co-printing of stiff and elastomeric materials must be explored

Proteoglycan composition in loaded and unloaded discs.

<p>Proteoglycan composition was evaluated by agarose gel electrophoresis in NP tissue of loaded (L) and unloaded (UL) IVDs after 14 days of culture. The IVDs were injected with 100 µg trypsin prior to loading. Equal amounts of GAG was loaded (n = 6 extracts per condition were pooled).</p

Stress profilometry.

<p>Comparison of average plateau pressures for control and trypsin-treated discs (p 0.07).</p

Culturing of intact loaded and unloaded IVDs.

<p><b>A</b>, The bioreactor system consists of two subsystems: culture chamber and loading frame. The IVDs are placed between porous platens attached to a piston. Media is circulated in through the top and bottom platens. The loading frame is a triple unit, with an pneumatic actuator controlled with a proportional pressure control valve. A load cell and linear variable displacement transformer measure load and displacement. The actuator is connected to the piston of the culture chamber. The system is computer controlled. <b>B</b>, The discs were cultured for 14 days unloaded (UL) or loaded (L) at 0.1 Hz as illustrated.</p

The influence of physiological load on proteoglycan synthesis in trypsin-treated discs.

<p>Proteoglycan content was evaluated by the DMMB assay in NP tissue of loaded and unloaded IVDs after 14 days of culture. The IVDs were injected with 0, 10 or 100 µg trypsin prior to loading. Proteoglycan content was normalized to tissue weight (n 6, error bars represent SEM) *p<0.05, **p<0.001.</p