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Orthopaedic Proceedings
Vol. 101-B, Issue SUPP_10 | Pages 4 - 4
1 Oct 2019
Partridge S Snuggs J Thorpe A Cole A Chiverton N Le Maitre C Sammon C
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Introduction

Injectable hydrogels via minimally invasive surgery offer benefits to the healthcare system, reduced risk of infection, scar formation and the cost of treatment. Development of new treatments with the use of novel biomaterials requires significant pre-clinical testing and must comply with regulations before they can reach the bedside. In the European economic area (EEA) one of the first hurdles of this process is attaining the CE marking which protects the health, safety and environmental aspects of a product. Implanted materials fall under the class III medical device EU745 regulation standards. To attain the CE marking for a product parties must provide evidence of the materials safety with an investigational medicinal product dossier (IMPD).

Methods and Results

We have been working to develop a new thermoresponsive injectable biomaterial hydrogel (NPgel) for the treatment of intervertebral disc (IVD) disease. A large part of the IMPD requires information on how the hydrogel physical properties change over time in bodily conditions. We have been studying 6 batches of NPgel over 18 months, tracking the materials wet/ dry weight, structure and composition. To date we have found that NPgel in liquids more similar to the body (with protein and salts) appear to be stable and safe, whilst those in distilled water swell and disintegrate over time. Subtle long-term changes to the material composition were found and we are currently investigating its ramifications.


Orthopaedic Proceedings
Vol. 101-B, Issue SUPP_10 | Pages 8 - 8
1 Oct 2019
Owen D Snuggs J Partridge S Sammon C Le Maitre C
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Introduction

We have developed a new synthetic hydrogel that can be injected directly into the intervertebral disc (IVD) without major surgery. Designed to improve fixation of joint prosthesis, support bone healing or improve spinal fusion, the liquid may support the differentiation of native IVD cells towards osteoblast-like cells cultured within the hydrogel. Here we investigate the potential of this gel system (Bgel) to induce bone formation within intervertebral disc tissue.

Methods

IVD tissue obtained from patients undergoing discectomy, or cadaveric samples, were cultured within a novel explant device. The hydrogel was injected, with and without mesenchymal stem cells (MSCs), and cultured under hypoxia, to mimic the degenerate IVD environment, for 4 weeks. Explants were embedded to wax and native cellular migration into the hydrogel was investigated, together with cellular phenotype and matrix deposition.


Orthopaedic Proceedings
Vol. 101-B, Issue SUPP_10 | Pages 45 - 45
1 Oct 2019
Partridge S Snugg J Michael A Cole A Chiverton N Sammon C Maitre C
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Introduction

Low back pain is the leading cause of musculoskeletal disease and the biggest cause of morbidity worldwide. Approximately 40% of these are cases are caused by disease of the intervertebral discs (IVDs): the shock absorbing, flexible material located between the bones (vertebrae) along the length of the spine. In severe cases, the spine becomes unstable and it becomes necessary to immobilise or fix the joint in position using a lumbar cage spacer between in the IVD and metal pins with supporting plates in the vertebrae. This is a complex, expensive, major surgery and it is associated with complications, such as spinal fusion failure and inappropriate implant position. These complications have a dramatic impact on the quality of life of the affected patients and the burden to society and the healthcare system is exacerbated.

Methods and Results

We present an in vitro study looking at the effect of our Bgel hydrogel on mesenchymal stem cells (MSCs) and their bone forming capacity within lumbar cages: devices used to space the bones apart in the fusion operation, as a mechanism to improve fixation and intra cage bone formation. MSCs were isolated from human hip joint, expanded, seeded within Bgel, cast into well inserts or lumbar cages and cultured for 4 weeks. Using 3D X-ray imaging micro computed tomography (μCT) scans we show that the MSC in the presence Bgel begin to mineralise within the lumbar cages. Histology is currently ongoing and will be presented at the meeting.


Orthopaedic Proceedings
Vol. 101-B, Issue SUPP_10 | Pages 17 - 17
1 Oct 2019
Snuggs J Thorpe A Partridge S Chiverton N Cole A Michael A Sammon C Le Maitre C
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Purpose of study and background

We have previously reported the development of injectable hydrogels for potential disc regeneration (NPgel) or bone formation which could be utilized in spinal fusion (Bgel). As there are multiple sources of mesenchymal stem cells (MSCs), this study investigated the incorporation of patient matched hMSCs derived from adipose tissue (AD) and bone marrow (BM) to determine their ability to differentiate within both hydrogel systems under different culture conditions.

Methods and Results

Human fat pad and bone marrow derived MSCs were isolated from femoral heads of patients undergoing hip replacement surgery for osteoarthritis with informed consent. MSCs were encapsulated into either NPgel or Bgel and cultured for up to 6 weeks in 5% (NPgel) or 21% (Bgel) O2. Histology and immunohistochemistry was utilized to determine phenotype. Both fat and bone marrow derived MSCs, were able to differentiate into both cell lineages. NPgel culture conditions increased expression of matrix components such as collagen II and aggrecan and NP phenotypic markers FOXF1 and PAX1, whereas Bgel induced expression of collagen I and osteopontin, indicative of osteogenic differentiation.


Orthopaedic Proceedings
Vol. 101-B, Issue SUPP_10 | Pages 36 - 36
1 Oct 2019
Partridge S Maitre C Sammon C
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Introduction

Musculoskeletal diseases are the biggest cause of morbidity worldwide, with low back pain (LBP) being the leading cause. Forty percent of LBP cases are caused by disease of shock absorbers in the spine known as intervertebral discs (IVDs). The IVDs enable the spine to twist and bend, whilst absorbing load during normal daily activities. The durability of this tissue is sustained by the cells of the spine and so during disease or mechanical damage these cells can behave abnormally further damaging the disc and stimulating local nerves causing extreme pain. Degradation of the intervertebral disc (IVD) currently has no preventative treatment; an injectable hydrogel biomaterial could reinforce disc mechanical properties and promote tissue regeneration.

Methods and Results

We present an injectable range of hydrogel biomaterials made from water, clay and polymer that set at 37°C. The materials were made at 80°C polymerised in water and stored at 70°C to remain liquid. The physical properties of the materials were assessed using various methods, including mechanical assessment using temperature-controlled rheometry to monitor the liquid-hydrogel transition.


Orthopaedic Proceedings
Vol. 101-B, Issue SUPP_10 | Pages 30 - 30
1 Oct 2019
Snuggs J Rustenberg C Emanuel K Partridge S Sammon C Smit T Le Maitre C
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Purpose of study and background

Low back pain affects 80% of the population at some point in their lives with 40% of cases attributed to intervertebral disc (IVD) degeneration. A number of potential regenerative approaches are under investigation worldwide, however their translation to clinic is currently hampered by an appropriate model for testing prior to clinical trials. Therefore, a more representative large animal model for IVD degeneration is needed to mimic human degeneration. Here we investigate a caprine IVD degeneration model in a loaded disc culture system which can mimic the native loading environment of the disc.

Methods and Results

Goat discs were excised and cultured in a bioreactor under diurnal, simulated-physiological loading (SPL) conditions, following 3 days pre load, IVDs were degenerated enzymatically for 2hrs and subsequently loaded for 10 days under physiological loading. A PBS injected group was used as controls. Disc deformation was continuously monitored and changes in disc height recovery quantified using stretched-exponential fitting. Histological staining was performed on caprine discs to assess extracellular matrix production and immunohistochemistry performed to determine expression of catabolic protein expression.

The injection of collagenase and cABC induced mechanical behavior akin to that seen in human degeneration. A decrease in collagens and glycosaminoglycans (GAGs) was seen in enzyme injected discs, which was accompanied by increased cellular expression for degradative enzymes and catabolic cytokines.


Orthopaedic Proceedings
Vol. 101-B, Issue SUPP_10 | Pages 22 - 22
1 Oct 2019
Snuggs J Thorpe A Hutson C Partridge S Chiverton N Cole A Sammon C Le Maitre C
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Purpose of study and background

IVD degeneration is a major cause of Low back pain. We have previously reported an injectable hydrogel (NPgel), which induces differentiation of human MSCs to disc cells and integrates with NP tissue following injection in vitro. However, the translation of this potential treatment strategy into clinic is dependent on survival and differentiation of MSCs into disc cells within the degenerate IVD. Here, we investigated the viability and differentiation of hMSCs incorporated into NPgel cultured under conditions mimicking the healthy and degenerate microenvironment of the disc.

Methods and Results

MSCs were cultured in NP gel under 5% O2 in either: standard culture (DMEM, pH7.4); healthy disc (DMEM, pH7.1); degenerate disc (low glucose DMEM, pH6) or degenerate disc plus IL-1β. Following 4 weeks histological staining and immunohistochemical analysis investigated viability, ECM synthesis and matrix degrading enzyme expression.

Here we have shown that viability and NP cell differentiation of MSCs incorporated within NPgel was mostly unaffected by treatment with conditions such as low glucose, low pH and the presence of cytokines, all regarded as key contributors to disc degeneration. In addition, the NPgel was shown to prevent MSCs from displaying a catabolic phenotype with low expression of degradative enzymes, highlighting the potential of NPgel to differentiate hMSCs and protect them from the degenerate disc microenvironment.


Orthopaedic Proceedings
Vol. 101-B, Issue SUPP_9 | Pages 22 - 22
1 Sep 2019
Thorpe A Partridge S Snuggs J Vickers L Charlton F Cole A Chiverton N Sammon C Le Maitre C
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Background

Intervertebral disc (IVD) degeneration is a major cause of low back pain (LBP). We have developed an injectable hydrogel (NPgel), which following injection into bovine IVD explants, integrates with IVD tissue and promotes disc cell differentiation of delivered mesenchymal stem cells (MSCs) without growth factors. Here, we investigated the injection of NPgel+MSCs into IVD explants under degenerate culture conditions.

Methods and Results

The NPgel integrated with bovine and human degenerate Nucleus Pulposus (NP) tissue and hMSCs produced matrix components: aggrecan, collagen type II and chondroitin sulphate in standard and degenerate culture conditions. Significantly increased cellular immunopositivty for aggrecan was observed within native NP cells surrounding the site where NPgel+MSCs were injected (P≤0.05). In NP explants a significant decrease in catabolic factors were observed where NPgel+MSCs was injected in comparison to controls.


Orthopaedic Proceedings
Vol. 101-B, Issue SUPP_9 | Pages 48 - 48
1 Sep 2019
Partridge S Thorpe A Le Maitre C Sammon C
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Introduction

Injectable hydrogels via minimally invasive surgery reduce the risk of infection, scar formation and the cost of treatment. Degradation of the intervertebral disc (IVD) currently has no preventative treatment. An injectable hydrogel material could restore disc height, reinforce local mechanical properties, and promote tissue regeneration. We present a hydrogel material Laponite® associated poly(N-isopropylacrylamide)-co-poly(dimethylacrylamide) (NPGel). Understanding how the components of this hydrogel system influence material properties, is crucial for tailoring treatment strategies for the IVD and other tissues.

Methods & Results

The effect of hydrogel wt./wt., clay and co-monomer percentages were assessed using a box-Behnken design. Rheometry, SEM, FTIR and swelling was used to measure changes in material properties in simulated physiological conditions. Rheometry revealed gelation temperature of hydrogel materials could be modified with dimethyl-acrylamide co-monomer; however, final maximum mechanical properties remained unaffected. Increasing the weight % and clay % increased resultant mechanical properties from ∼500–2500 G' (Pa), increased viscosity, but retained the ability to flow through a 26G needle at 39°C.


Orthopaedic Proceedings
Vol. 100-B, Issue SUPP_15 | Pages 17 - 17
1 Nov 2018
Dalgarno K Benning M Partridge S Tulah A Ahmed S Dickinson A Genever P Pearson R Feichtinger G Loughlin J Ferreira-Duarte A
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This paper reports on a proof of concept project funded by the UK National Council for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs), with the aim of developing an in vitro model to recapitulate the human osteoarthritic joint, based on a multiple human cell type co-culture system, for research and drug development in OA. The targets were: (i) the development of a cell culture platform that could produce a mixed stable cell culture of cell types that represent the key components of the human joint: synoviocytes – type I and type II; osteoblasts; osteoclasts; chondrocytes/cartilage or cartilage-like matrix; adipocytes; and immune cells. (ii) demonstration of cell phenotype stability and viability for at least 72 hours. In order to establish the cell culture platform we have developed an eight-channel cell printer, capable of accurately and reliably printing the required cell types to create osteochondral and synovial cell types within a transwell system. Two different sets of cells have been developed and processed using the cell printer: a set based on using an immortalised hTERT MSC line to create osteoblasts, chondrocytes and adipocytes, with commercial cells lines providing the other cell types, and a set obtained from tissue excised during orthopaedic surgery. This gives both a repeatable set of cells with which to undertake mode of action studies, and a bank of cell sets which will be representative of different stages of osteoarthritis. The co-cultures have been immunohistochemically assessed in order to demonstrate maintenance of phenotype.


Orthopaedic Proceedings
Vol. 98-B, Issue SUPP_4 | Pages 18 - 18
1 Jan 2016
Brockett C Smyth A Day M Harris N Partridge S Williams S Fisher J
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Introduction

Total ankle replacement (TAR) has been used as a surgical intervention for arthritis since the 1970s. However, unlike clinically successful hip and knee replacements, TARs are renowned for extensive contraindications to surgery and high failure rates with an average of 83% survival at 5 years. The majority cite aseptic loosening as the reason for failure. The aim of this study wais to analyse retrieved TARs visually and through interferometry to identify potential the failure mechanisms associated with these devices.

Methods

Retrieved total ankle replacements (n=11) from consecutive revision surgeries carried out at Chapel Allerton Hospital, Leeds between August 2012 and January 2014, were collected for study at the University of Leeds, under an NRES approved procedure (09/H1307/60).

The bearing surfaces of the samples were visually inspected for evidence of damage and wear. The bearing surfaces between the tibial component and the flat surface of the polyethylene insert were then examined using a scanning white light interferometer (NP Flex, Bruker, USA). It was not possible to characterise the talar bearing surface or the inferior polyethylene surface at this stage through interferometry due to the curvature of the surface. The components were aligned and five sections on each of the surfaces measured. These sections represented; anterior-medial, anterior-lateral, posterior-medial, posterior lateral and central regions of the bearing surfaces. 3D roughness values were recorded, and the mean 3D surface roughness compared between implants. Measurements were taken on the medial and lateral aspects of the bearing surfaces to investigate whether damage was location specific. A coefficient of determination was calculated to assess the relationship between implantation time and surface roughness.