Abstract

Due to limitations of existing pharmacological therapies for the management of chronic pain in osteoarthritis (OA), surgical interventions remain a major component of current standard of care, with total joint replacements (TJRs) considered for people who have not responded adequately to conservative treatment. This study aimed to quantify the economic burden of moderate-to-severe chronic pain in patients with OA in England prior to TJR.

A retrospective, longitudinal cohort design was employed using Clinical Practice Research Datalink GOLD primary care data linked to Hospital Episode Statistics secondary care data in England. Patients (age ≥18 years) with an existing OA diagnosis of any anatomical site (Read/ICD-10) were indexed (Dec-2009 to Nov-2017) on a moderate-to-severe pain event (which included TJR) occurring within an episode of chronic pain. 5-year TJR rates from indexing were assessed via Kaplan-Meier estimates. All-cause healthcare resource utilisation and direct medical costs were evaluated in the 1–12 and 13–24 months prior to the first TJR experienced after index. Statistical significance was assessed via paired t-tests.

The study cohort comprised 5,931 eligible patients (57.9% aged ≥65 years, 59.2% female). 2,176 (36.7%) underwent TJR (knee: 54.4%; hip: 42.8%; other: 2.8%). The 5-year TJR rate was 45.4% (knee: 24.3%; hip: 17.5%; other: 6.8%). Patients experienced more general practitioner consultations in 1–12 months pre-TJR compared with 13–24 months pre-TJR (means: 12.13 vs. 9.61; p<0.0001), more outpatient visits (6.68 vs. 3.77; p<0.0001), more hospitalisations (0.74 vs. 0.62; p=0.0032), and more emergency department visits (0.29 vs. 0.25, p=0.0190). Total time (days) spent as an inpatient was higher in 1–12 months pre-TJR (1.86 vs. 1.07; p<0.0001). Mean total per-patient cost pre-TJR increased from £1,771 (13–24 months) to £2,621 (1–12 months) (p<0.0001).

Resource-use and costs incurred were substantially greater in the 12 months immediately prior to TJR, compared with 13–24 months prior. Reasons for increased healthcare and economic burden in the pre-TJR period deserve further exploration as potential targets for efforts to improve patient experience and efficiency of care.

Background and Purpose: Current clinical guidelines recommend supervised exercise as a first-line treatment in the management of low back pain (LBP). To date studies have not used objective forms of measuring changes in free-living physical activity (FLPA). The aim of this study was to compare FLPA between two groups who received either supervised exercise and auricular acupuncture (EAA) or exercise alone (E).

Methods: 51 patients with non-specific LBP [mean±SD=42.8±12.4 years] wore an accelerometer for 7 days at baseline, end of the intervention (week 8) and follow up (week 25). FLPA variables were extracted: % time (hours) spent in postures; daily step count and cadence. Data were analysed using SPSS (v15). Repeated measures ANCOVA were performed using a mixed linear model.

Results: There was no difference in daily step count between the two groups at any time point (E, mean±SD, week 1, 8197±2187; week 8, 8563±2438, week 25, 8149±2800; EAA, mean±SD, week 1, 8103±1942; week 8, 8010±2845, week 25, 8139±1480, p=0.9) or cadence. No differences in postures were noted, apart from time sitting/lying which was shorter at week 25 in the E group (p=0.006).

Conclusions & Implications: Supervised exercise classes, with or without acupuncture, do not produce changes in FLPA in the short term or longer term in people with LBP. This suggests more effective ways should be sought to encourage the patient to incorporate activity into their daily lives. These findings have informed the design of two walking intervention trials for LBP patients.

Conflict of Interest: None

Sources of Funding: Research and Development Office, Northern Ireland, Strategic Priority Fund, Department of Employment and Learning, Northern Ireland.

Aim: Severity of knee osteoarthritis (OA) can be defined clinically, radiologically, or pathologically. The Système Française D’Arthroscopie (SFA) is a validated method of grading and scoring the severity of changes on the articular surface as observed through the arthroscope. We have validated a modification of the SFA system for use with digital photographs of pathological samples.

Material and Method: After Ethics Committee approval, both tibial plateaux and femoral condyles were collected from 84 patients undergoing total knee replacement or at post mortem. Extent and grading of cartilage changes were documented for the 4 compartments of each sample on a diagram using direct visualisation and probing (Pathological Scores). In addition, each sample was digitally photographed at standard magnification and illumination, archived, graded and scored (Photographic Scores). A second observer (AY) also graded and scored photographic images for 72 compartments of the first 18 cases.

Data analysis: Repeatability was measured as Repeatability Coefficients (Bland and Altman, Lancet1986; 1; 307–10). 95% of the differences between 2 measurements of a case are expected to fall within the Repeatability Coefficient. Associations between compartments are expressed as Pearson correlation coefficients.

Results: For each of the 4 compartments studied, scores ranged from -2.2 to +717.8, representing the full range of possible scores. Allocation of scores to diagrams was highly repeatable (Repeatability Coefficient = 50). There was good agreement between Pathological and Photographic Scores (Repeatability Coefficient = 88). There was moderate agreement between Photographic Scores allocated by the 2 observers, with greatest agreement for low (< 200) and high (> 500) scores. Scores for each compartment correlated with scores for each of the other 3 compartments (R values 0.7 to 0.9, all P < 0.005).

Conclusion: Our modified SFA system permits scoring of OA severity using digital photographs of pathological samples. Our data support the view that OA affects the entire joint, and that a single compartment (e.g. medial tibial plateau) can be taken as broadly representative of the tibiofemoral joint as a whole.

The ability to generate replacement human tissues on demand is a major clinical need. Indeed the paucity of techniques in reconstructive surgery and trauma emphasize the urgent requirement for alternative strategies for the formation of new tissues and organs. The idea of biomimesis is to abstract good design principles and optimizations from nature and incorporate them in the construction of synthetic materials and structures. Direct appropriation of natural inorganic skeletons is also biomimetic since their unique properties inform us on ways to generate functional, optimized scaffolds.

A number of well characterized natural skeletons were investigated as potential scaffolds for tissue regeneration using mesenchymal stem cell populations. Marine sponges, sea urchin skeletons and nacre were found to possess unique functional properties that supported human cell attachment, growth and proliferation and provided organic/ inorganic extracellular matrix analogues for guided tissue regeneration.

A good understanding of the processses involved in biomineralisation and the emergence of complex inorganic forms has inspired synthetic strategies for the formation of biological analogues (organised inorganic materials with biological form). We have developed two functional examples of biological structures generated using biomimetic materials chemistry with applications for human tissue regeneration. Mineralised biopoly-saccharide microcapsules provided enclosed micro-environments with an appropriate physical structure and physiological milieu, for the support of the initial stages of tissue regeneration combined with a capacity to deliver human cells, plasmid DNA and controlled release of biological factors such as cytokines. Calcium carbonate porous microspheres analogous to microscopic coccolithophore shells provided a template for tissue formation and a mechanism for the delivery of DNA and functional biological factors. These biomi-metic structures have considerable potential as scaffolds for skeletal repair and regeneration, particularly when combined with inductive and stimulatory biological factors (cytokines, morphogens, signal molecules) and plasmid DNA carrying with them chemical cues that modulate and direct permanent tissue formation complimentary with the host.

Aim: The Système Française D’Arthroscopie (SFA) is a validated method of arthroscopic grading and scoring the knee OA. We have validated a modification of the SFA system for use with digital photographs of pathological samples.

Material and Method: After Ethics Committee approval, both tibial plateaux and femoral condyles were collected from 84 patients undergoing total knee replacement or at post mortem. Extent and grading of cartilage changes were documented for the 4 compartments of each sample on a diagram using photographs at standard magnification and illumination, archived, (Photographic Scores). Validation obtained by direct visualisation and probing (Pathological Scores). Radiographic and Histological scoring In addition, each sample was digitally. A second observer (AY) also graded and scored photographic images for 72 compartments of the first 18 cases.

Results: For each of the 4 compartments studied, scores ranged from -2.2 to +717.8, representing the full range of possible scores. A statistically significant correlation observed in the study between radiological variables and the severity of chondropathy assessed by our (SFA-path) [ P < 0.005] suggests satisfactory extrinsic validity of this scoring system. And statistically significant correlation [p> 0.0001] between the SFA Path scores of the medial compartment tibial plateau OA and Histologi-cal grade [Minkin] of the same samples. Allocation of scores to diagrams was highly repeatable (Repeatability Coefficient = 50). There was good agreement between Pathological and Photographic Scores (Repeatability Coefficient = 88). There was moderate agreement between Photographic Scores allocated by the 2 observers, with greatest agreement for low (< 200) and high (> 500) scores. Scores for each compartment correlated with scores for each of the other 3 compartments (R values 0.7 to 0.9, all P < 0.005).

Conclusion: We validated our modified SFA system which permits scoring of OA severity using digital photographs of pathological samples. SFApath is reliable and repeatable scoring system Our data support the view that OA affects the entire joint, and that a single compartment (e.g. medial tibial plateau) can be taken as broadly representative of the tibiofemoral joint as a whole.

Introduction: The ability to generate bone for skeletal repair, replacement or restoration is a major clinical need. Indeed the paucity of techniques in reconstructive surgery and trauma emphasise the need for alternative bone formation strategies. Natural biological ceramic structures possess arrangements of structural elements that govern and optimise tissue function, nutrition and organisation. The aim of this study was to fabricate biomineral microporous shells with highly complex forms and to examine their ability to interact with human osteoprogenitor cells as cell and growth factor delivery vehicles.

Methods: Microporous vaterite shells were generated using a synthetic in-solution mineralisation technique in which mineral is spontaneously deposited around vesicular templates (Walsh and Mann 1999)* Porous and textured self-organising hollow microspheres (5–20 _m) were generated expressing controlled and uniform shapes. These micropores puncture the surface at high densities and are interconnected throughout the sphere. Primary human bone marrow cells labelled with Cell Tracker Green and ethidium homodimer-1 fluorescent labels and osteoprogenitors transfected with an adenoviral vector expressing Green Fluorescent Protein (AdGFP) were cultured with vaterite shells over three weeks.

Results: Cell biocompatibility of these biomimetic spheres was confirmed by confocal fluorescence and light microscopy in primary human bone marrow cultures labelled with CTG and bone marrow cultures transfected with AdGFP. At three weeks microspheres were encapsulated and integrated with osteoprogenitor cells. Histological analysis confirmed expression of alkaline phosphatase, extracellular matrix synthesis and the capacity for extensive mineralisation. Examination by SEM, fluorescent and light microscopy showed that the growth of osteoprogenitors transfected with AdGFP and microspheres in pellet culture showed vaterite spheres were encapsulated and integrated within the osteoprogenitor cell matrix indicating the potential of growth factor delivery. To determine the potential of the spheres to encapsulate selected proteins, microporous spheres were incubated with bovine haemoglobin. FITC microscopic evidence showed haemoglobin could be entrapped inside the spheres and between the biomineral crystal plates during self-assembly.

Discussion and Conclusion: These studies demonstrate the development of facile techniques for the generation of porous microsphere sponges that are biocompatible, possess the ability to aid mineralisation and for the delivery of cell and growth factors. These calcium carbonate structures provide a material with widespread application in a range of tissue engineering applications including skeletal tissue regeneration.

Introduction: The clinical need for a biodegradable material with broad application is evidenced by the fact that tissue loss as a result of injury or disease provides reduced quality of life for many at significant socio-economic cost. The development of simple biodegradable materials, with broad applicability and tissue/ cell specificity has to date proved elusive. Natural biopolymers such as alginate and chitosan are structural biomaterials of increasing significance to tissue repair and regeneration due to their potential for fabrication, design and efficient, environmentally benign synthesis. We describe the development of innovative microcapsule scaffolds based on chitosan and alginate that can be tailored to a range of cell types for a variety of tissues.

Methods: Semi-permeable polysaccharide microcapsules were produced by a one-step method, in which the deposition of a semi-permeable alginate/chitosan membrane around droplets of sodium alginate was coupled with in-situ precipitation of amorphous calcium phosphate as described by Leveque et al (2002)*. A variety of human cell types including mesenchymal stem cells, osteoprogenitors selected using the STRO-1 antibody by magnetically activated cell separation (MACS), osteoprogenitors transfected with adenovirus expressing Green Fluorescent Protein (GFP) and chondrocytes were mixed with sodium alginate and encapsulated within alginate/chitosan and calcium phosphate.

Results: Hybrid spheres (750–10,000um) were generated encapsulating primary human osteoprogenitor cells, STRO-1 selected osteoprogenitors and AdGFP transfected osteoprogenitors. Encapsulated cells remain viable inside the polysaccharide microcapsules for 2 weeks as shown by positive alkaline phosphatase staining of encapsulated cells. Cells expressing GFP were observed within microspheres indicating the e ability to deliver cells/factors as well as the potential for gene therapy. Encapsulation and delivery of active BMP-2 was confirmed using the promyoblast cell line C2C12 known to be exquisitely sensitive to BMP-2. Nucleation of calcium phosphate occurred within the polysaccharide membrane and could be controlled by the phosphate concentration in the alginate droplets to produce hybrid microcapsules with enhanced mechanical strength. Thin walled capsules were shown to split and degrade in culture within 2–4 days releasing viable osteoprogenitor cells indicating the ability to manipulate the mechanical integrity and to programme degradation of the microspheres. Finally we have shown that aggregation of the microspheres into extended frameworks can be achieved using a designed droplet/vapour aerosol system resulting in foams of aggregated beads.

Discussion and Conclusion: A variety of human skeletal cells have been encapsulated within polysaccharide/ calcium phosphate microspheres and extended frameworks with specifiable dimensions. These composite scaffolds offer stable mechanical and chemical biomimetic environments conducive to normal cell function. Natural polysaccharides are also highly amenable to complexation with a range of bioactive molecules and consequently offer tremendous potential in tissue engineering and regeneration of hard and soft tissues.