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Orthopaedic Proceedings
Vol. 106-B, Issue SUPP_1 | Pages 10 - 10
2 Jan 2024
Tian X Vater C Raina DB Findeisen L Matuszewski L Tägil M Lidgren L Schaser K Disch A Zwingenberger S
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Although bone morphogenetic protein 2 (BMP-2) has been FDA-approved for spinal fusion for decades, its disadvantages of promoting osteoclast-based bone resorption and suboptimal carrier (absorbable collagen sponge) leading to premature release of the protein limit its clinical applications. Our recent study showed an excellent effect on bone regeneration when BMP-2 and zoledronic acid (ZA) were co-delivered based on a calcium sulphate/hydroxyapatite (CaS/HA) scaffold in a rat critical-size femoral defect model. Therefore, the aim of this study was to evaluate whether local application of BMP-2 and ZA released from a CaS/HA scaffold is favorable for spinal fusion. We hypothesized that CaS/HA mediated controlled co-delivery of rhBMP-2 and ZA could show an improved effect in spinal fusion over BMP-2 alone. 120, 8-week-old male Wistar rats (protocol no. 25-5131/474/38) were randomly divided into six groups in this study (CaS/HA, CaS/HA + BMP-2, CaS/HA + systemic ZA, CaS/HA + local ZA, CaS/HA + BMP-2 + systemic ZA, CaS/HA + BMP-2 + local ZA). A posterolateral spinal fusion at L4 to L5 was performed bilaterally by implanting group-dependent scaffolds. At 3 weeks and 6 weeks, 10 animals per group were euthanized for µCT, histological staining, or mechanical testing. µCT and histological results showed that the CaS/HA + BMP-2 + local ZA group significantly promoted bone regeneration than other treated groups. Biomechanical testing showed breaking force in CaS/HA + BMP + local ZA group was significantly higher than other groups at 6 weeks. In conclusion, the CaS/HA-based biomaterial functionalized with bioactive molecules rhBMP-2 and ZA enhanced bone formation and concomitant spinal fusion outcome

Acknowledgements: Many thanks to Ulrike Heide, Anna-Maria Placht (assistance with surgeries) as well as Suzanne Manthey & Annett Wenke (histology).


Orthopaedic Proceedings
Vol. 105-B, Issue SUPP_9 | Pages 92 - 92
17 Apr 2023
Raina D Mrkonjic F Tägil M Lidgren L
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A number of techniques have been developed to improve the immediate mechanical anchorage of implants for enhancing implant longevity. This issue becomes even more relevant in patients with osteoporosis who have fragile bone. We have previously shown that a dynamic hip screw (DHS) can be augmented with a calcium sulphate/hydroxyapatite (CaS/HA) based injectable biomaterial to increase the immediate mechanical anchorage of the DHS system to saw bones with a 400% increase in peak extraction force compared to un-augmented DHS. The results were also at par with bone cement (PMMA). The aim of this study was to investigate the effect of CaS/HA augmentation on the integration of a different fracture fixation device (gamma nail lag-screw) with osteoporotic saw bones.

Osteoporotic saw bones (bone volume fraction = 15%) were instrumented with a gamma nail without augmentation (n=8) or augmented (n=8) with a CaS/HA biomaterial (Cerament BVF, Bonesupport AB, Sweden) using a newly developed augmentation method described earlier. The lag-screws from both groups were then pulled out at a displacement rate of 0.5 mm/s until failure. Peak extraction force was recorded for each specimen along with photographs of the screws post-extraction. A non-parametric t-test was used to compare the two groups.

CaS/HA augmentation of the lag-screw led to a 650% increase in the peak extraction force compared with the controls (p<0.01). Photographs of the augmented samples shows failure of the saw-bones further away from the implant-bone interface indicating a protective effect of the CaS/HA material.

We present a novel method to enhance the immediate mechanical anchorage of a lag-screw to osteoporotic bone and it is also envisaged that CaS/HA augmentation combined with systemic bisphosphonate treatment can lead to new bone formation and aid in the reduction of implant failures and re-operations.


Orthopaedic Proceedings
Vol. 105-B, Issue SUPP_8 | Pages 66 - 66
11 Apr 2023
Sebastian S Collin M Liu Y Raina D Tägil M Lidgren L
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There is a lack of carriers for the local delivery of rifampicin (RIF), one of the cornerstone second defence antibiotic for Staphylococcus aureus deep bone infections (DBIs). RIF is also associated with systemic side effects, and known for causing rapid development of antibiotic resistance when given as monotherapy. We evaluated a clinically usedbi-phasic calcium sulphate/hydroxyapatite (CaS/HA) biomaterial as a carrier for dual delivery of RIF with vancomycin (VAN) or gentamicin (GEN). It was hypothesized that this combined approach could provide improved biofilm eradication and prevent the development of RIF resistance.

Methods: 1) Biofilm eradication: Using a modified crystal violet staining biofilm quantification method, the antibiotics released at different time points (Day 1, 3, 7, 14, 21, 28 and 35) from the hemispherical pellets of CaS/HA(500 mg)-VAN (24.57 mg) / GEN (10.35 mg) composites with or without RIF (8.11 mg) were tested for their ability to disrupt the preformed 48-h old biofilms of S. aureus ATCC 25923, and S. aureus clinical strain P-3 in 96-well microtitre plate. For each tested group of antibiotic fractions, five separate wells were used (n=5). 2) Testing for resistance development: Similar to the method mentioned above the 48-h biofilm embeded bacteria exposed to antibiotic fractions from different time points continuously for 7 days. The biofilms remained were then tested for RIF resistant strains of bacteria.

Overall, there was clear antibiofilm biofilm activity observed with CaS/HA-VAN/GEN+RIF combinations compared with CaS/HA-VAN/GEN alone. The S. aureus strains developed resistance to RIF when biofilms were subjected to CaS/HA-RIF alone but not with combinations of CaS/HA-VAN/GEN+RIF

Enhanced antibiofilm effects without development of RIF resistance indicates that biphasic CaS/HA loaded with VAN or GEN could be used as a carrier for RIF for additional local delivery in clinically demanding DBIs.

Acknowledgement: We deeply acknowledge the Royal Fysiographic Society of Lund, Landshövding Per Westlings Minnesfond and the Stina and Gunnar Wiberg fond for financial support.


Orthopaedic Proceedings
Vol. 105-B, Issue SUPP_8 | Pages 55 - 55
11 Apr 2023
Raina D Markeviciute V Arvidsson L Törnquist E Stravinskas M Kok J Jacobson I Liu Y Tengattini A Sezgin E Vater C Zwingenberger S Isaksson H Tägil M Tarasevicius S Lidgren L
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Majority of osteoporosis related fractures are treated surgically using metallic fixation devices. Anchorage of fixation devices is sometimes challenging due to poor osteoporotic bone quality that can lead to failure of the fracture fixation.

Using a rat osteoporosis model, we employed neutron tomography and histology to study the biological effects of implant augmentation using an isothermally setting calcium sulphate/hydroxyapatite (CaS/HA) biomaterial with synthetic HA particles as recruiting moiety for systemically administered bisphosphonates. Using an osteoporotic sawbones model, we then provide a standardized method for the delivery of the CaS/HA biomaterial at the bone-implant interface for improved mechanical anchorage of a lag-screw commonly used for hip fracture fixation. As a proof-of-concept, the method was then verified in donated femoral heads and in patients with osteoporosis undergoing hip fracture fixation.

We show that placing HA particles around a stainless-steel screw in-vivo, systemically administered bisphosphonates could be targeted towards the implant, yielding significantly higher peri-implant bone formation compared to un-augmented controls. In the sawbones model, CaS/HA based lag-screw augmentation led to significant increase (up to 4 times) in peak extraction force with CaS/HA performing at par with PMMA. Micro-CT imaging of the CaS/HA augmented lag-screws in cadaver femoral heads verified that the entire length of the lag-screw threads and the surrounding bone was covered with the CaS/HA material. X-ray images from fracture fixation surgery indicated that the CaS/HA material could be applied at the lag-screw-bone interface without exerting any additional pressure or risk of venous vascular leakage.: We present a new method for augmentation of lag-screws in fragile bone. It is envisaged that this methodcould potentially reduce the risk of fracture fixation failure especially when HA seeking “bone active” drugs are used systemically.


Bone & Joint Research
Vol. 11, Issue 11 | Pages 787 - 802
1 Nov 2022
Sebastian S Tandberg F Liu Y Raina DB Tägil M Collin M Lidgren L

Aims

There is a lack of biomaterial-based carriers for the local delivery of rifampicin (RIF), one of the cornerstone second defence antibiotics for bone infections. RIF is also known for causing rapid development of antibiotic resistance when given as monotherapy. This in vitro study evaluated a clinically used biphasic calcium sulphate/hydroxyapatite (CaS/HA) biomaterial as a carrier for dual delivery of RIF with vancomycin (VAN) or gentamicin (GEN).

Methods

The CaS/HA composites containing RIF/GEN/VAN, either alone or in combination, were first prepared and their injectability, setting time, and antibiotic elution profiles were assessed. Using a continuous disk diffusion assay, the antibacterial behaviour of the material was tested on both planktonic and biofilm-embedded forms of standard and clinical strains of Staphylococcus aureus for 28 days. Development of bacterial resistance to RIF was determined by exposing the biofilm-embedded bacteria continuously to released fractions of antibiotics from CaS/HA-antibiotic composites.


Orthopaedic Proceedings
Vol. 103-B, Issue SUPP_4 | Pages 100 - 100
1 Mar 2021
Raina D Liu Y Isaksson H Tägil M Lidgren L
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Targeted delivery of drugs is a major challenge in diseases such as infections and tumors. The aim of this study was to demonstrate that hydroxyapatite (HA) particles can act as a recruiting moiety for various bioactive molecules and as a proof-of-concept demonstrate that the affinity of drugs to hydroxyapatite can exert a biological effect. A bisphosphonate, zoledronic acid (ZA), was used as a model drug. Experiment 1 (ZA seeks HA): Calcium sulphate (CaS)/hydroxyapatite (HA) biomaterial pellets (diameter¸=5 mm, height=2 mm) were implanted in the abdominal muscle pouch of rats. After 2-weeks of implantation, a sub-cutaneous injection of 14C-ZA (0.1 mg/kg) was given. 24 h later, the animals were sacrificed and the uptake of ZA determined in the pellets using scintillation counting. Experiment 2 (Systemically administered ZA seeks HA and exerts a biological effect): A fenestrated implant was filled with the CaS/HA biomaterial and inserted in the proximal tibia of rats. 2-weeks post-op, a subcutaneous injection of ZA (0.1 mg/kg) was given. Animals were sacrificed at 6-weeks post-op. Empty implant was used as a control. Peri-implant bone formation was evaluated using different techniques such as micro-CT, mechanical testing and histology. Welch's t-test was used for mechanical testing and Mann-Whitney U test for micro-CT data analysis. Experiment 1: Uptake of radioactive ZA in the CaS/HA biomaterial was confirmed. Almost no ZA was present in the surrounding muscle. These results show high specific binding between systemically administered ZA and synthetic particulate HA. Experiment 2: Significantly higher peri-implant bone was measured using micro-CT in the group wherein the implant contained the CaS/HA biomaterial and ZA was administered systemically (This study presents a method for biomodulating HA in situ by different bioactive molecules. The approach of implanting a biomaterial capable of recruiting systemically given drugs and thereby activate the material is novel and may present a possibility to treat bone infections or tumors.


Bone & Joint Research
Vol. 9, Issue 10 | Pages 709 - 718
1 Oct 2020
Raina DB Liu Y Jacobson OLP Tanner KE Tägil M Lidgren L

Bone is a dynamic tissue with a quarter of the trabecular and a fifth of the cortical bone being replaced continuously each year in a complex process that continues throughout an individual’s lifetime. Bone has an important role in homeostasis of minerals with non-stoichiometric hydroxyapatite bone mineral forming the inorganic phase of bone. Due to its crystal structure and chemistry, hydroxyapatite (HA) and related apatites have a remarkable ability to bind molecules. This review article describes the accretion of trace elements in bone mineral giving a historical perspective. Implanted HA particles of synthetic origin have proved to be an efficient recruiting moiety for systemically circulating drugs which can locally biomodulate the material and lead to a therapeutic effect. Bone mineral and apatite however also act as a waste dump for trace elements and drugs, which significantly affects the environment and human health.

Cite this article: Bone Joint Res 2020;9(10):709–718.


Bone & Joint Research
Vol. 8, Issue 2 | Pages 49 - 54
1 Feb 2019
Stravinskas M Nilsson M Vitkauskiene A Tarasevicius S Lidgren L

Objectives

The aim of this study was to analyze drain fluid, blood, and urine simultaneously to follow the long-term release of vancomycin from a biphasic ceramic carrier in major hip surgery. Our hypothesis was that there would be high local vancomycin concentrations during the first week with safe low systemic trough levels and a complete antibiotic release during the first month.

Methods

Nine patients (six female, three male; mean age 75.3 years (sd 12.3; 44 to 84)) with trochanteric hip fractures had internal fixations. An injectable ceramic bone substitute, with hydroxyapatite in a calcium sulphate matrix, containing 66 mg of vancomycin per millilitre, was inserted to augment the fixation. The vancomycin elution was followed by simultaneously collecting drain fluid, blood, and urine.


Orthopaedic Proceedings
Vol. 100-B, Issue SUPP_17 | Pages 44 - 44
1 Dec 2018
Stravinskas M Tarasevicius S Vitkauskiene A Nilsson M Lidgren L
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Aim

In vivo studies have shown a preventive and curative effect of using an injectable vancomycin containing biphasic ceramic in an osteomyelitis model. No clinical long term pharmacokinetic release study has been reported. Inadequate concentration in target tissues results in treatment failure and selection pressure for antibiotic-resistant organisms.

Our hypothesis was that vancomycin in the first week would reach high local concentrations but with low systemic levels.

Method

9 patients (6 women, 3 men) with trochanteric hip fractures classified as A1 and A2 according to the AO-classification all had internal fixations. The mean age was 75.3 years (± S.D. 12.3 years, range 44–84y). An injectable ceramic with hydroxyapatite embedded in a calcium sulphate matrix containing 66mg vancomycin per mL augmented the fixation. A mean of 9.7 mL (± S.D. 0.7 mL, range 8–10mL) was used. The elution of vancomycin was followed by collecting drain fluid, blood (4 days) and urine (4 weeks)


Orthopaedic Proceedings
Vol. 100-B, Issue SUPP_15 | Pages 33 - 33
1 Nov 2018
Raina D Qayoom I Larsson D Zheng M Kumar A Isaksson H Lidgren L Tägil M
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Metaphyseal fracture healing is important in joint-adjacent fractures and appears to differ from diaphyseal healing. We recently found that a biomaterial delivering bone morphogenic protein-2 (BMP-2) and zoledronic acid (ZA) healed the metaphyseal bone in a tibial defect but failed closing the cortical defect. In this study we added a BMP-2 soaked collagen membrane to study cortical healing from the muscle tissue surrounding the bone. We used SD rats and a 4.5 mm metaphyseal circular tibial defect. In group 1 (G1), a porous gelatin-calcium sulphate-hydroxyapatite (GCH) biomaterial containing rhBMP-2 and ZA was used to fill the defect (GCH+5 μg BMP-2+10 μg ZA). In group 2 (G2), we used a collagen membrane (2 μg BMP-2) to cover the GCH filled defect (GCH+3μg BMP+10 μg ZA). Group 3 (G3) was an empty control. Animals were sacrificed after 8-weeks and bone regeneration was evaluated with micro-CT and histology. In both G1 (P<0.001) and G2 (p<0.001) a significantly higher mineralized volume was found in the defect compared to empty G3. In G2 higher mineralized volume was found in the cortical region compared to both G1 (p<0.01) and G3 (p<0.001) as seen via micro-CT. Histologically, G1 and G2 showed islands of trabecular bone in the defect peripherally but only G2 showed cortical healing. G3 was empty in the middle but showed healed cortex. In conclusion, GCH can be used to deliver BMP-2 and ZA to promote metaphyseal bone growth. A membrane (CM) doped with low dose BMP-2 improved cortical regeneration.


Bone & Joint Research
Vol. 7, Issue 10 | Pages 548 - 560
1 Oct 2018
Qayoom I Raina DB Širka A Tarasevičius Š Tägil M Kumar A Lidgren L

During the last decades, several research groups have used bisphosphonates for local application to counteract secondary bone resorption after bone grafting, to improve implant fixation or to control bone resorption caused by bone morphogenetic proteins (BMPs). We focused on zoledronate (a bisphosphonate) due to its greater antiresorptive potential over other bisphosphonates. Recently, it has become obvious that the carrier is of importance to modulate the concentration and elution profile of the zoledronic acid locally. Incorporating one fifth of the recommended systemic dose of zoledronate with different apatite matrices and types of bone defects has been shown to enhance bone regeneration significantly in vivo. We expect the local delivery of zoledronate to overcome the limitations and side effects associated with systemic usage; however, we need to know more about the bioavailability and the biological effects. The local use of BMP-2 and zoledronate as a combination has a proven additional effect on bone regeneration. This review focuses primarily on the local use of zoledronate alone, or in combination with bone anabolic factors, in various preclinical models mimicking different orthopaedic conditions.

Cite this article: I. Qayoom, D. B. Raina, A. Širka, Š. Tarasevičius, M. Tägil, A. Kumar, L. Lidgren. Anabolic and antiresorptive actions of locally delivered bisphosphonates for bone repair: A review. Bone Joint Res 2018;7:548–560. DOI: 10.1302/2046-3758.710.BJR-2018-0015.R2.


Orthopaedic Proceedings
Vol. 100-B, Issue SUPP_12 | Pages 41 - 41
1 Oct 2018
Robertsson O Sundberg M W-Dahl A Lidgren L
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Background

The modern modular implants allow surgeons to combine different combinations of components within the same brand of which some may have completely different design.

During 1999–2012 the same cemented femur component was used together with a cemented stemmed tibia baseplate and also against a cemented pegged tibia baseplate. We decided to compare the revision rate of total knee arthroplasties (TKAs) using these two tibia baseplates.

Methods

This is a register study. During 1999–2012, 32,429 cemented, CR TKA's of a specific brand were reported to the Swedish Knee Arthroplasty Register (SKAR). The part numbers for the femur, tibia and insert (in modular implants) were available in 99.2% of cases. The most common combination used the cemented CR femur against a cemented stemmed baseplate in 50.3% of cases while the same CR femur was used against a cemented pegged baseplate in 8.3% of cases, mainly at two hospitals. In order to make the material more comparable, only patients having osteoarthritis (OA) were included and only TKAs using two types of regular constraint inserts and in which the patella had been left un-resurfaced. Chi-Square test was used to investigate gender distribution in the groups and t-test for the mean age at surgery. Kaplan Meier analysis and the log-rank test were used to evaluate the risk of revision until the end of 2016. A p-value <0.05 was considered statistically significant.


Orthopaedic Proceedings
Vol. 100-B, Issue SUPP_4 | Pages 46 - 46
1 Apr 2018
Raina DB Isaksson H Tägil M Lidgren L
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Background

The doses of local rhBMP-2 in commercially available materials are high with known drawbacks such as inflammation and premature bone resorption. The latter can be prevented by adding bisphosphonates like zoledronic acid (ZA) but systemic ZA has side effects and patient adherence to treatment is low. In a recent study, we have shown that local co-delivery of rhBMP-2 and ZA via a calcium sulphate/hydroxyapatite (CS-HA) biomaterial can be used to regenerate both cortical and trabecular bone in a rat model of metaphyseal bone defect. Even low doses of local ZA in the biomaterial showed promising results and increased bone formation within the defect compared to the controls. A step before clinical translation of the local treatment regimen is to evaluate the in-vivo release kinetics of these additives and thus in this study, we aimed to investigate the in-vivo pharmacokinetics of rhBMP-2 and ZA from the CS-HA biomaterial in a rat abdominal muscle pouch model over a period of 4-weeks.

Methods

In-vivo release kinetics of 125I labeled rhBMP-2 and 14C labeled ZA was performed using an abdominal muscle pouch model in rats (n=6). Both rhBMP-2 and ZA were labeled commercially with a radiochemical purity of >95%. The detection of 125I -rhBMP-2 release was performed by implanting pellets of the CS-HA biomaterial containing 125I -rhBMP-2 and ZA and the same animals followed over a period of 4-weeks (day 1, 3, 7, 14, 21& 28) using SPECT imaging. Similarly, the 14C-ZA was detected by implanting CS-HA pellets containing rhBMP-2 and 14C-ZA. Release was detected via scintillation counting and at each time point (Day 1, 7, 14& 28) 6-animals were sacrificed.


Orthopaedic Proceedings
Vol. 99-B, Issue SUPP_22 | Pages 27 - 27
1 Dec 2017
Stefánsdóttir A Thompson O Sundberg M W-Dahl A Lidgren L Robertsson O
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Aim

Patients reporting penicillin allergy do often receive clindamycin as systemic antibiotic prophylaxis. The effect of clindamycin has however not been compared to antibiotics with proven effect in joint arthroplasty surgery. The aim of the study was to reveal if there were differences in the rate of revision due to infection after total knee arthroplasty (TKA) depending on which antibiotic was used as systemic prophylaxis.

Method

Patients reported to the Swedish Knee Arthroplasty Register having a TKA performed due to osteoarthritis (OA) during the years 2009 – 2015 were included in the study. The type of prophylactic antibiotic is individually registered. For 80,018 operations survival statistics were used to calculate the rate of revision due to infection until the end of 2015, comparing the group of patients receiving the beta-lactam cloxacillin with those receiving clindamycin as systemic prophylaxis.


Orthopaedic Proceedings
Vol. 98-B, Issue SUPP_23 | Pages 17 - 17
1 Dec 2016
Stravinskas M Horstmann PF Hettwer W Nilson M Tarasevicius S Petersen MM Lidgren L
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Aim

The demand for a synthetic bone substitute that can build bone and at the same time kill bacteria is high. The aim of this study was to compare the elution of gentamicin from a new synthetic bone substitute in vitro with the performance in clinical applications.

Method

Gentamicin release was measured from a synthetic bone graft substitute, comparing in vitro and clinical conditions:

elution in Ringers solution. The bone graft substitute contained 175mg gentamicin per 10mL. The material was introduced either as paste or as pre-set beads with a high or low surface areas, >100cm2 and 24cm2 respectively. The gentamycin release was measured by daily collection of samples.

elution in patients treated for trochanteric hip fractures(n=6) or uncemented hip revisions(n=5) 7,3±1,1mL of substitute was implanted and drainage was collected at 6h,12h,24h,30h,36h post-op. Blood serum was collected every hour for the first 6h and thereafter every 6h until 4 days post-op, urine – daily for the first 7 days post-op.

elution in patients treated after bone tumor resection(n=8), 12,1±5,5mL of substitute was implanted and both drainage and blood serum were collected daily until 2 days post-op.

Gentamicin concentrations were analyzed using antibody technique.


Bone & Joint Research
Vol. 5, Issue 10 | Pages 500 - 511
1 Oct 2016
Raina DB Gupta A Petersen MM Hettwer W McNally M Tägil M Zheng M Kumar A Lidgren L

Objectives

We have observed clinical cases where bone is formed in the overlaying muscle covering surgically created bone defects treated with a hydroxyapatite/calcium sulphate biomaterial. Our objective was to investigate the osteoinductive potential of the biomaterial and to determine if growth factors secreted from local bone cells induce osteoblastic differentiation of muscle cells.

Materials and Methods

We seeded mouse skeletal muscle cells C2C12 on the hydroxyapatite/calcium sulphate biomaterial and the phenotype of the cells was analysed. To mimic surgical conditions with leakage of extra cellular matrix (ECM) proteins and growth factors, we cultured rat bone cells ROS 17/2.8 in a bioreactor and harvested the secreted proteins. The secretome was added to rat muscle cells L6. The phenotype of the muscle cells after treatment with the media was assessed using immunostaining and light microscopy.


Bone & Joint Research
Vol. 5, Issue 9 | Pages 427 - 435
1 Sep 2016
Stravinskas M Horstmann P Ferguson J Hettwer W Nilsson M Tarasevicius S Petersen MM McNally MA Lidgren L

Objectives

Deep bone and joint infections (DBJI) are directly intertwined with health, demographic change towards an elderly population, and wellbeing.

The elderly human population is more prone to acquire infections, and the consequences such as pain, reduced quality of life, morbidity, absence from work and premature retirement due to disability place significant burdens on already strained healthcare systems and societal budgets.

DBJIs are less responsive to systemic antibiotics because of poor vascular perfusion in necrotic bone, large bone defects and persistent biofilm-based infection. Emerging bacterial resistance poses a major threat and new innovative treatment modalities are urgently needed to curb its current trajectory.

Materials and Methods

We present a new biphasic ceramic bone substitute consisting of hydroxyapatite and calcium sulphate for local antibiotic delivery in combination with bone regeneration. Gentamicin release was measured in four setups: 1) in vitro elution in Ringer’s solution; 2) local elution in patients treated for trochanteric hip fractures or uncemented hip revisions; 3) local elution in patients treated with a bone tumour resection; and 4) local elution in patients treated surgically for chronic corticomedullary osteomyelitis.


Orthopaedic Proceedings
Vol. 97-B, Issue SUPP_16 | Pages 24 - 24
1 Dec 2015
Raina D Gupta A Petersen M Hettwer W Nally M Tägil M Zheng M Kumar A Lidgren L
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To demonstrate the role of an antibiotic containing bone substitute, native bone active proteins and muscle transforming into bone.

Recurrent osteomyelitis was eradicated and filled with a gentamycin eluting bone substitute (Cerament™l G) consisting of sulphate and apatite phases and covered by a muscle flap.

C2C12 muscle cells were seeded on the bone substitute in-vitro and their phenotype was studied.

Another muscle cell line L6 was seeded with osteoblast conditioned medium containing bone active proteins and specific markers were studied for bone differentiation.

A chronic, longstanding, fistulating osteomyelitis was operated with radical eradication and filling of the cavity with gentamycin eluting bone substitute. At one year, the patient had no leg pain and a healed wound. Significant bone was also seen in the overlaying muscle, at one month post-op disappearing after 6-months. Local delivery of gentamycin had a protective effect on bone formation.

C2C12 cells seeded on the gentamycin eluting bone substitute depicted no difference in proliferation when compared to plain bone substitute and expressed 4 folds higher Alkaline phosphatase (ALP) compared to controls.

C2C12 cells expressed proteins and genes coding for collagen type 1 (Col 1), osteocalcin (OCN), osteopontin (OPN) and bonesialoprotein (BSP).

L6 cells cultured with osteoblast conditioned medium remained uninucleated and expressed osteoblastic proteins like Col 1, OCN, OPN and BSP.

Bone substitute with gentamycin leads to differentiation of mesenchymal cells into bone in-vitro.

Native bone active proteins from an osteoblast culture can induce differentiation of muscle cells in-vitro.

Clinical observations with rapid bone formed in the bone substitute and in some cases in the muscle are a consequence of both leakage of bone active proteins and also from osteoprogenitor cells coming from the overlaying muscle interacting with the osteoinductive bone substitute.


Orthopaedic Proceedings
Vol. 97-B, Issue SUPP_15 | Pages 45 - 45
1 Dec 2015
W-Dahl A Stefánsdóttir A Sundberg M Lidgren L Robertsson O
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To reveal if patient reported knee-related pain, function, quality of life, general health and satisfaction at one year after primary total knee arthroplasty (TKA) is different between patients not being subject to revision surgery and those having had early treatment with open debridement and exchange of the tibial insert for postoperative PJI.

The Swedish Knee Arthroplasty Register was used to identify 50 patients in the region of Skane that had a primary TKA during the years 2008 – 2012 and within 6 months were revised with open debridement and exchange of the tibial insert due to suspected or verified PJI. Only patients without further revisions were included. Patient reported outcome measurements (PROM) were obtained preoperatively and 1 year postoperatively and included knee related pain, function, quality of life using the Knee injury and Osteoarthritis Outcome Score (KOOS), general health using the EQ-VAS as well as satisfaction with the surgery. The scores were compared to those reported by 3,913 patients having a TKA during the same time but not revised during the first year. Welch's t-test and the Chi2-test were used in statistical analysis.

Compared to the controls the infected patients were older (mean age 72 vs 69 years, p = 0.04) and were more morbid (ASA 3; 14/50 patients vs 14%, p = 0.02). The preoperative PROM data were similar. Complete 1 year PROM data was available for 31 of the patients. Those patients reported somewhat worse outcome one year postoperatively than the controls with statistically and clinically significant differences in general health (mean 61 vs 76, p=0.002), KOOS ADL (mean 65 vs 76, p=0.03) and knee related quality of life (mean 51 vs 63, p=0.02) with large variations on individual level. Just over half of the patients (17/29) treated for PJI were very satisfied or satisfied with the surgery compared to 79% of the controls.

Patients treated with open debridement and exchange of the tibial insert due to early PJI after primary TKA reported less beneficial postoperative outcome than those without revision surgery during the first postoperative year but with large individual variations.


The Bone & Joint Journal
Vol. 96-B, Issue 9 | Pages 1222 - 1226
1 Sep 2014
W-Dahl A Sundberg M Lidgren L Ranstam J Robertsson O

We identified a group of patients from the Swedish Arthroplasty Register who reported no relief of pain or worse pain one year after a total knee replacement (TKR). A total of two different patient-reported pain scores were used during this process. We then evaluated how the instruments used to measure pain affected the number of patients who reported no relief of pain or worse pain, and the relative effect of potential risk factors.

Between 2008 and 2010, 2883 TKRs were performed for osteoarthritis in two Swedish arthroplasty units. After applying exclusion criteria, 2123 primary TKRs (2123 patients) were included in the study. The Knee injury and Osteoarthritis Outcome Score (KOOS) and a Visual Analogue Scale (VAS) for knee pain were used to assess patients pre-operatively and one year post-operatively.

Only 50 of the 220 patients (23%) who reported no pain relief on either the KOOS pain subscale or the VAS for knee pain did so with both of these instruments. Patients who reported no pain relief on either measure tended to have less pain pre-operatively but a higher degree of anxiety. Charnley category C was a predictor for not gaining pain relief as measured on a VAS for knee pain.

The number of patients who are not relieved of pain after a TKR differs considerably depending on the instrument used to measure pain.

Cite this article: Bone Joint J 2014;96-B:1222–6.


Bone & Joint Research
Vol. 3, Issue 7 | Pages 217 - 222
1 Jul 2014
Robertsson O Ranstam J Sundberg M W-Dahl A Lidgren L

We are entering a new era with governmental bodies taking an increasingly guiding role, gaining control of registries, demanding direct access with release of open public information for quality comparisons between hospitals. This review is written by physicians and scientists who have worked with the Swedish Knee Arthroplasty Register (SKAR) periodically since it began. It reviews the history of the register and describes the methods used and lessons learned.

Cite this article: Bone Joint Res 2014;3:217–22.


Bone & Joint Research
Vol. 3, Issue 3 | Pages 48 - 50
1 Mar 2014
Lidgren L Gomez-Barrena E N. Duda G Puhl W Carr A


Orthopaedic Proceedings
Vol. 92-B, Issue SUPP_IV | Pages 543 - 543
1 Oct 2010
W-Dahl A Davidson D Graves S Lidgren L Miller L Robertsson O
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Introduction: In recent years some countries have shown increasing interest and use of unicompartmental knee arthroplasty (UKA). Several studies have reported increasing use of UKA for osteoarthritis in younger patients with low revision rates. The aim of this study was to determine the outcome of UKA by combining two national databases containing prospectively collected data.

Method: Over 50 000 UKA procedures were analyzed to determine the cumulative percentage revision (CPR). Any reason for revision was used as the end point. The analysis was stratified according to age, gender and type of prosthesis to determine outcomes in patients younger than 65 years

Result: In this study both countries showed declining use of UKA in terms of the proportion of knee replacement procedures and of absolute numbers undertaken per year. The seven year CPR of UKA in patients younger than 65 years was 16.2%, and at 10 years was 17.5%. No significant difference was found between gender, however outcome did vary depending on the type of prosthesis used.

Conclusion: This study reports the outcomes from the two largest databases of UKA. Within 10 years of UKA a substantial number of revisions were seen in patients younger than 65 years, with varying results depending on the type of prosthesis used.


The Journal of Bone & Joint Surgery British Volume
Vol. 90-B, Issue 12 | Pages 1558 - 1561
1 Dec 2008
Ranstam J Wagner P Robertsson O Lidgren L

Public disclosure of outcome-orientated ranking of hospitals is becoming increasingly popular and is routinely used by Swedish health-care authorities. Whereas uncertainty about an outcome is usually presented with 95% confidence intervals, ranking’s based on the same outcome are typically presented without any concern for bias or statistical precision. In order to study the effect of incomplete registration of re-operation on hospital ranking we performed a simulation study using published data on the two-year risk of re-operation after total hip replacement.

This showed that whereas minor registration incompleteness has little effect on the observed risk of revision, it can lead to major errors in the ranking of hospitals. We doubt whether a level of data entry sufficient to generate a correct ranking can be achieved, and recommend that when ranking hospitals, the uncertainties about data quality and random events should be clearly described as an integral part of the results.


The Journal of Bone & Joint Surgery British Volume
Vol. 90-B, Issue 1 | Pages 7 - 10
1 Jan 2008
Lidgren L

This paper considers the increased risk of the development of lymphoma in patients with chronic inflammatory disease who undergo metal-on-metal arthroplasty.


The Journal of Bone & Joint Surgery British Volume
Vol. 89-B, Issue 5 | Pages 599 - 603
1 May 2007
Robertsson O Stefánsdòttir A Lidgren L Ranstam J

Patients with osteoarthritis undergoing knee replacement have been reported to have an overall reduced mortality compared with that of the general population. This has been attributed to the selection of healthier patients for surgery. However, previous studies have had a maximum follow-up time of ten years. We have used information from the Swedish Knee Arthroplasty Register to study the mortality of a large national series of patients with total knee replacement for up to 28 years after surgery and compared their mortality with that of the normal population. In addition, for a subgroup of patients operated on between 1980 and 2002 we analysed their registered causes of death to determine if they differed from those expected.

We found a reduced overall mortality during the first 12 post-operative years after which it increased and became significantly higher than that of the general population. Age-specific analysis indicated an inverse correlation between age and mortality, where the younger the patients were, the higher their mortality. The shift at 12 years was caused by a relative over-representation of younger patients with a longer follow-up. Analysis of specific causes of death showed a higher mortality for cardiovascular, gastrointestinal and urogenital diseases. The observation that early onset of osteoarthritis of the knee which has been treated by total knee replacement is linked to an increased mortality should be a reason for increased general awareness of health problems in these patients.


The Journal of Bone & Joint Surgery British Volume
Vol. 86-B, Issue 7 | Pages 958 - 961
1 Sep 2004
Dreinhöfer KE Féron J Herrera A Hube R Johnell O Lidgren L Miles K Panarella L Simpson H Wallace WA


The Journal of Bone & Joint Surgery British Volume
Vol. 86-B, Issue 1 | Pages 120 - 125
1 Jan 2004
Nilsson M Wang J Wielanek L Tanner KE Lidgren L

An injectable material consisting of calcium sulphate mixed with hydroxyapatite was investigated as a possible alternative to autograft in the restoration of bone defects. The material was studied both in vitro in simulated body fluid (SBF) and in vivo when implanted in rat muscles and into the proximal tibiae of rabbits. Variation in the strength and weight of the material during ageing in SBF was measured. Tissue response, material resorption and bone ingrowth were studied in the animal models.

A good tissue response was observed in both the rat muscles and rabbit tibiae without inflammatory reactions or the presence of fibrous tissue. Ageing in SBF showed that during the first week carbonated hydroxyapatite precipitated on the surfaces of the material and this may enhance bone ingrowth.


The Journal of Bone & Joint Surgery British Volume
Vol. 84-B, Issue 6 | Pages 908 - 914
1 Aug 2002
Yuan X Ryd L Tanner KE Lidgren L

We present a new approach for the accurate reconstruction of three-dimensional skeletal positions using roentgen single-plane photogrammetric analysis (RSPA). This technique uses a minimum of three markers embedded in each segment which allow continuous, real-time, internal skeletal movement to be measured from single-plane images, provided that the precise distance between the markers is known.

A simulation study indicated that the error propagation in this approach is influenced by focus position, object position, the number of control points, the accuracy of the previous measurement of the distance between markers and the accuracy of image measurement. For reconstruction of normal movement of the knee with an input measurement error of sd = 0.02 mm, the rotational and translational differences between reconstructed and original movement were less than 0.27° and 0.9 mm, respectively.

Our results showed that the accuracy of RSPA is sufficient for the analysis of most movement of joints. This approach can be applied in combination with force measurements for dynamic studies of the musculoskeletal system.


The Journal of Bone & Joint Surgery British Volume
Vol. 83-B, Issue 3 | Pages 339 -
1 Apr 2001
Dunbar MJ Robertsson O Ryd L Lidgren L

The Swedish Knee Arthroplasty Registry (SKAR) has recorded knee arthroplasties prospectively in Sweden since 1975. The only outcome measure available to date has been revision status. While questionnaires on health outcome may function as more comprehensive endpoints, it is unclear which are the most appropriate. We tested various outcome questionnaires in order to determine which is the best for patients who have had knee arthroplasty as applied in a cross-sectional, discriminative, postal survey.

Four general health questionnaires (NHP, SF-12, SF-36 and SIP) and three disease/site-specific questionnaires (Lequesne, Oxford-12, and WOMAC) were tested on 3600 patients randomly selected from the SKAR. Differences were found between questionnaires in response rate, time required for completion, the need for assistance, the efficiency of completion, the validity of the content and the reliability. The mean overall ranks for each questionnaire were generated. The SF-12 ranked the best for the general health, and the Oxford-12 for the disease/site-specific questionnaires. These two questionnaires could therefore be recommended as the most appropriate for use with a large knee arthroplasty database in a cross-sectional population.


The Journal of Bone & Joint Surgery British Volume
Vol. 83-B, Issue 1 | Pages 45 - 49
1 Jan 2001
Robertsson O Knutson K Lewold S Lidgren L

A total of 10474 unicompartmental knee arthroplasties was performed for medial osteoarthritis in Sweden between 1986 and 1995. We sought to establish whether the number of operations performed in an orthopaedic unit affected the incidence of revision. Three different implants were analysed: one with a high revision rate, known to have unfavourable mechanical and design properties; a prosthesis which is technically demanding with a known increased rate of revision; and the most commonly used unicompartmental device.

Most of the units performed relatively few unicompartmental knee arthroplasties per year and there was an association between the mean number carried out and the risk of later revision. The effect of the mean number of operations per year on the risk of revision varied. The technically demanding implant was most affected, that most commonly used less so, and the outcome of the unfavourable design was not influenced by the number of operations performed.

For unicompartmental arthroplasty, the long-term results are related to the number performed by the unit, probably expressing the standards of management in selecting the patients and performing the operation.


The Journal of Bone & Joint Surgery British Volume
Vol. 78-B, Issue 6 | Pages 861 - 862
1 Nov 1996
Fulford P Lidgren L


The Journal of Bone & Joint Surgery British Volume
Vol. 77-B, Issue 6 | Pages 862 - 864
1 Nov 1995
Franzen H Toksvig-Larsen S Lidgren L Onnerfalt R

We report the preliminary findings of the use of roentgen stereophotogrammetric analysis to evaluate the early migration of five femoral components after revision for mechanical loosening using impacted cancellous allograft and cement. All hips were examined at one week, four to six months and one year after surgery. All the components subsided by 0.4 to 4.9 mm during the first year. In four hips the prosthetic head was displaced 1.1 to 6.9 mm posteriorly. Fixation of the femoral components was less secure than after primary arthroplasty but the incidence and magnitude of early migration were similar to those after revision with cement alone.


The Journal of Bone & Joint Surgery British Volume
Vol. 68-B, Issue 5 | Pages 795 - 803
1 Nov 1986
Knutson K Lindstrand A Lidgren L

A prospective nation-wide study of knee arthroplasty has been under way in Sweden since October 1975. By the end of 1983, 4505 arthroplasties for osteoarthritis and 3495 for rheumatoid arthritis had been recorded and reviewed one, three and six years after the operation. Using actuarial methods, the probability of the prosthesis remaining in situ after six years was calculated. In osteoarthritis this probability ranged from 65% for hinged prostheses to 90% for medial compartment prostheses. Two-and three-compartment prostheses produced intermediate results with 87% survival. In rheumatoid arthritis the probability varied from 72% for medial compartment prostheses to 90% for two- and three-compartment prostheses. The main reason for failure was loosening of the components, the second most common was infection. The probability of revision for infection by six years was 2% in osteoarthritis and 3% in rheumatoid arthritis. Most revisions were to a three-compartment prosthesis. Knee fusion at primary revision was required in 2% of the cases at six years.


The Journal of Bone & Joint Surgery British Volume
Vol. 68-B, Issue 2 | Pages 223 - 228
1 Mar 1986
Rydholm U Elborgh R Ranstam J Schroder A Svantesson H Lidgren L

We report 60 synovectomies of the knee in 51 children with juvenile chronic arthritis. Synovitis had been present for an average of 5 years and the average age at operation was 13 years. Results were evaluated in terms of pain, knee movement, relapse of synovitis and radiological change during a follow-up averaging 7.5 years. The relief of pain was rewarding and there was a slight postoperative gain in range of knee movement in most cases. The older the patient at onset of disease, the greater the risk of pain during follow-up. Progressive joint destruction was more common in younger patients, those with systemic or polyarticular disease, and those with highly active disease at the time of operation. Recurrence of synovitis was more frequent in patients who had their operation in a phase of high disease activity; this occurred most often in patients with polyarticular disease.


The Journal of Bone & Joint Surgery British Volume
Vol. 67-B, Issue 1 | Pages 47 - 52
1 Jan 1985
Knutson K Lindstrand A Lidgren L

Twenty consecutive patients treated by arthrodesis for failed knee arthroplasty are reviewed. Eight hinged, five stabilised and seven compartmental prostheses were removed, for infection (15 cases), loosening (4) and instability (1). One patient refused a second-stage operation but the remainder gained sound fusion. Infected knees had a two-stage procedure with temporary insertion of gentamicin-loaded beads after removal of the prosthesis; all infections healed. Six arthrodeses using a Hoffmann-Vidal external fixator resulted in two temporary failures. One Ace-Fischer external fixation was successful. Of 10 primary attempts at arthrodesis with an intramedullary Kuntscher nail, nine were successful; the tenth fused after two more attempts by the same method. The two failures of external fixation and two failures after Charnley single-frame compression done elsewhere were successfully fused with intramedullary nails. Delayed union in three cases fused after prolonged fixation and repeated bone grafts. The indications for and methods of arthrodesis after failed knee arthroplasty are discussed.


The Journal of Bone & Joint Surgery British Volume
Vol. 66-B, Issue 5 | Pages 737 - 741
1 Nov 1984
Rydholm U Tjornstrand B Pettersson H Lidgren L

Fifteen patients with rheumatoid arthritis had 19 elbow arthroplasties with the Wadsworth type of surface replacement prosthesis. After a follow-up period averaging 30 months, 11 patients with 15 elbow arthroplasties were entirely satisfied with their freedom from pain and range of movement. Radiologically, however, the humeral component was loose in 10 of the 19 elbows and the ulnar component in 5. Two patients had reoperation, one to remove a prosthesis for early deep infection and one to exchange a humeral component which was loose. The risk of mechanical loosening is reduced by accurate positioning of the humeral component, but there is a high potential for failure. Changes in the design of the prosthesis and better instrumentation for alignment of the components are desirable. Prosthetic replacement of the elbow should still be regarded as experimental.


The Journal of Bone & Joint Surgery British Volume
Vol. 64-B, Issue 3 | Pages 295 - 299
1 Jun 1982
Mogensen B Brattstrom H Ekelund L Svantesson H Lidgren L