RESUMEN
Osteoarthritis (OA) is a common cause of pain and disability. Local corticosteroid injections are effective in treating OA pain and inflammation but are short-acting. Prolonged intra-articular (IA) corticosteroid exposure may even lead to cartilage deterioration. The aim of this prospective study was to assess safety and provide proof-of-concept of IA-applied biodegradable polyesteramide-based microspheres (PEAMs) gradually releasing triamcinolone acetonide (TA). Mimicking continuous exposure associated with local drug delivery in canine articular chondrocytes cultured in the continuous presence of TA tissue regeneration was not affected, whereas intermittent exposure reduced proteoglycan production. In this respect, TA-PEAMs administered IA in a proof-of-concept study in 12 client-owned dogs with established OA also showed safety by radiographic examination, without changes in OA severity and in glycosaminoglycan synovial fluid levels. Treatment also resulted in clinical improvement in 10 out of 11 dogs during the two-month follow-up period, which persisted in 6 out of 10 dogs after 6 months, based on objective gait analysis and owner questionnaires. Synovial prostaglandin E2, a pro-inflammatory marker, was decreased two months after treatment. This study showed safety and proof-of-concept of IA-administered TA-PEAMs in dogs with OA, as a first step towards translation into the veterinary and human clinic.
RESUMEN
Back pain affects millions globally and in 40% of the cases is attributed to intervertebral disc degeneration. Oral analgesics are associated with adverse systemic side-effects and insufficient pain relief. Local drug delivery mitigates systemic effects and accomplishes higher local dosing. Clinical efficacy of intradiscally injected celecoxib (CXB)-loaded polyesteramide microspheres (PEAMs) was studied in a randomized prospective double-blinded placebo controlled veterinary study. Client-owned dog patients suffering from back pain were treated with CXB-loaded (n = 20) or unloaded PEAMs ("placebo") (n = 10) and evaluated by clinical examination, gait analysis, owners' questionnaires, and MRI at 6 and 12 weeks follow-up. At 6 and 12 weeks, CXB-treated dogs experienced significantly less pain interference with their daily life activities compared to placebo. The risk ratio for treatment success was 1.90 (95% C.I. 1.24-2.91, p = 0.023) at week 6 and 1.95 (95% C.I. 1.10-3.45, p = 0.036) at week 12. The beneficial effects of CXB-PEAMs were more pronounced for the subpopulation of male dogs and those with no Modic changes in MRI at inclusion in the study; disc protrusion did not affect the outcome. It remains to be determined whether intradiscal injection of CXB-PEAMs, in addition to analgesic properties, has the ability to halt the degenerative process in the long term or restore the disc.
RESUMEN
Inflammation of the synovium and joint capsule is a main driver of pain in an osteoarthritic (OA) joint. Triamcinolone acetonide (TAA) is a classical corticosteroid that reduces synovitis and alleviates pain, albeit transiently. Biomaterial-based local TAA release may prolong the suppression of pain without the need for multiple injections. Polylactic-co-glycolic acid (PLGA) formulations of TAA prolong OA pain relief to a limited extent. A novel polyesteramide (PEA) microsphere platform allows for extended release in the OA joint for over 3 months. To evaluate their effect on pain and inflammation, TAA-loaded microspheres were intra-articularly delivered to the knee joint in a rat model of acute arthritis induced by intra-articular injection of streptococcal cell wall peptidoglycan-polysaccharide (PGPS) and subsequent flare-ups by intravenous PGPS injections. PEA-loaded microspheres were benchmarked with TAA-loaded PLGA microspheres and bolus TAA injection. TAA treatments were injected intra-articularly before the first induced flare-up. TAA-loaded PEA and PLGA microspheres reduced joint swelling and signs of pain-like behavior over the entire study period, as assessed by weight bearing and referred mechanical hypersensitivity, whereas bolus suspension was effective for a shorter time period. TAA-loaded PEA microspheres reduced lameness to a greater extent than TAA-loaded PLGA microspheres. In conclusion, a single intra-articular injection of TAA-loaded PEA microspheres reduced joint swelling and induced longer pain relief compared to bolus injection. Hence relief of inflammation and pain by PEA-based delivery of TAA may prove to be effective and durable.
Asunto(s)
Materiales Biocompatibles/farmacología , Inflamación/tratamiento farmacológico , Osteoartritis/tratamiento farmacológico , Dolor/tratamiento farmacológico , Triamcinolona Acetonida/farmacología , Resinas Acrílicas/química , Animales , Materiales Biocompatibles/química , Modelos Animales de Enfermedad , Femenino , Inyecciones Intraarticulares/métodos , Articulación de la Rodilla/efectos de los fármacos , Microesferas , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Ratas , Ratas Sprague-Dawley , Membrana Sinovial/efectos de los fármacos , Triamcinolona Acetonida/químicaRESUMEN
Episodes of inflammation and pain are predominant features of arthritic joint diseases. Drug delivery systems (DDS) could reduce inflammation and pain long-term without chances of infection upon multiple injections. To allow for long-term evaluation of DDS, we modified a previously published acute arthritis model by extending follow-up periods between flare-ups. Unilateral synovial inflammation of the knee was induced by intra-articular injection of streptococcal cell wall peptidoglycan polysaccharide (PGPS), and flare-ups were induced by intravenous PGPS injections every 4 weeks for a total duration of 84 days. In PGPS-reactivated animals, joint swelling, pain behavior, post mortem synovitis, and osteophyte formation were notable features. Hepatitis, splenitis and inflammation of non-primed joints were observed as systemic side effects. To test the applicability of the modified arthritis model for long-term testing of DDS, the duration of anti-inflammatory and analgesic effects of a corticosteroid released from two different polymer-based platforms was evaluated. The current modified arthritis model has good applicability for testing of DDS for a prolonged period of time. Furthermore, the novel autoregulatory polyesteramide (PEA) microsphere platform releasing triamcinolone acetonide (TAA) was benchmarked against poly lactic-co-glycolic acid (PLGA) and reduced joint swelling and pain behavior more potently compared to TAA-loaded PLGA microspheres.
RESUMEN
BACKGROUND CONTEXT: Local corticosteroids have been used to relieve symptoms of chronic low back pain, although treatment effects have been shown to wear off relatively fast. Prolonging corticosteroid presence by controlled release from biomaterials may allow for longer pain relief while circumventing adverse effects such as high bolus dosages. PURPOSE: The purpose of this study was to evaluate the safety and efficacy of intradiscal controlled release of triamcinolone acetonide (TAA) by poly(esteramide) microspheres in a canine degenerated intervertebral disc (IVD) model. STUDY DESIGN: In a preclinical experimental large animal model, the effect of prolonged glucocorticoid exposure on disc degeneration was evaluated. METHODS: Degeneration was accelerated by nucleotomy of lumbar IVDs of Beagle dogs. After 4 weeks, microspheres loaded with 8.4 µg TAA, and 0.84mg TAA were administered to the degenerated IVDs by intradiscal injection (n=6 per group). Empty microspheres (n=6) and all adjacent non-nucleotomized noninjected IVDs were included as controls (n=24). Immediately prior to TAA administration and after 12 weeks, magnetic resonance imaging was performed. Degenerative changes were evaluated by disc height index, Pfirrmann grading, T1ρ and T2 mapping values, postmortem CT scans, macroscopic and microscopic grading, and biochemical/immunohistochemical analysis of inflammation and extracellular matrix content. In addition, nerve growth factor (NGF) protein expression, a biomarker for pain, was scored in nucleus pulposus (NP) tissues. The study was funded by a research grant from Health Holland (1.3million eurosâ¯=â¯1.5million US dollars). RESULTS: Macroscopic evaluation and CT images postmortem were consistent with mild disc degeneration. Other abnormalities were not observed. Nucleotomy-induced degeneration and inflammation was mild, reflected by moderate Pfirrmann grades and PGE2 levels. Regardless of TAA dosage, local sustained delivery did not affect disc height index nor Pfirrmann grading, T1ρ and T2 mapping values, PGE2 tissue levels, collagen, GAG, and DNA content. However, the low dosage of TAA microspheres significantly reduced NGF immunopositivity in degenerated NP tissue. CONCLUSIONS: This is the first in vivo application in a preclinical large animal model of a controlled release formulation of corticosteroids in mild IVD degeneration. Sustained release of TAA locally in the IVD appeared safe and reduced NGF expression, suggesting its potential applicability for pain relief, although beneficial effects were absent on tissue degeneration. CLINICAL SIGNIFICANCE: The present platform seems to be promising in extending the local controlled delivery of TAA with the potency to provide long-standing analgesia in the subset of LBP patients suffering from discogenic pain.
Asunto(s)
Antiinflamatorios/administración & dosificación , Portadores de Fármacos/efectos adversos , Degeneración del Disco Intervertebral/tratamiento farmacológico , Microesferas , Triamcinolona Acetonida/administración & dosificación , Animales , Antiinflamatorios/uso terapéutico , Perros , Portadores de Fármacos/química , Matriz Extracelular/metabolismo , Femenino , Masculino , Núcleo Pulposo/metabolismo , Triamcinolona Acetonida/uso terapéuticoRESUMEN
BACKGROUND AND PURPOSE: Corticosteroids are intra-articularly injected to relieve pain in joints with osteoarthritis (OA) or acute tissue damage such as ligament or tendon tears, despite its unverified contraindication in unstable joints. Biomaterial-based sustained delivery may prolong reduction of inflammatory pain, while avoiding harmful peak drug concentrations. EXPERIMENTAL APPROACH: The applicability of prolonged corticosteroid exposure was examined in a rat model of anterior cruciate ligament and medial meniscus transection (ACLT + pMMx) with ensuing degenerative changes. KEY RESULTS: Intra-articular injection of a bolus of the corticosteroid triamcinolone acetonide (TAA) resulted in enhanced joint instability in 50% of the joints, but neither instability-induced OA cartilage degeneration, synovitis, nor the OA-related bone phenotype was affected. However, biomaterial microsphere-based extended TAA release enhanced instability in 94% of the animals and induced dystrophic calcification and exacerbation of cartilage degeneration. In healthy joints, injection with TAA releasing microspheres had no effect at all. In vitro, TAA inhibited cell migration out of joint tissue explants, suggesting inhibited tissue healing in vivo as mechanisms for enhanced instability and subsequent cartilage degeneration. CONCLUSIONS AND IMPLICATIONS: We conclude that short-term TAA exposure has minor effects on surgically induced unstable joints, but its extended presence is detrimental by extending instability and associated joint degeneration through compromised healing. This supports a contraindication of prolonged corticosteroid exposure in tissue damage-associated joint instability, but not of brief exposure.
Asunto(s)
Inestabilidad de la Articulación/tratamiento farmacológico , Osteoartritis/tratamiento farmacológico , Triamcinolona Acetonida/efectos adversos , Cicatrización de Heridas/efectos de los fármacos , Animales , Materiales Biocompatibles/administración & dosificación , Materiales Biocompatibles/efectos adversos , Modelos Animales de Enfermedad , Femenino , Inyecciones Intraarticulares , Inestabilidad de la Articulación/cirugía , Microesferas , Osteoartritis/metabolismo , Osteoartritis/cirugía , Ratas , Ratas Sprague-Dawley , Triamcinolona Acetonida/administración & dosificación , Triamcinolona Acetonida/uso terapéuticoRESUMEN
Controlled biomaterial-based corticosteroid release might circumvent multiple injections and the accompanying risks, such as hormone imbalance and muscle weakness, in osteoarthritic (OA) patients. For this purpose, microspheres were prepared from an amino acid-based polyester amide (PEA) platform and loaded with triamcinolone acetonide (TAA). TAA loaded microspheres were shown to release TAA for over 60days in PBS. Furthermore, the bioactivity lasted at least 28days, demonstrated by a 80-95% inhibition of PGE2 production using TNFα-stimulated chondrocyte culture, indicating inhibition of inflammation. Microspheres loaded with the near infrared marker NIR780-iodide injected in healthy rat joints or joints with mild collagenase-induced OA showed retention of the microspheres up till 70days after injection. After intra-articular injection of TAA-loaded microspheres, TAA was detectable in the serum until day seven. Synovial inflammation was significantly lower in OA joints injected with TAA-loaded microspheres based on histological Krenn scores. Injection of TAA-loaded nor empty microspheres had no effect on cartilage integrity as determined by Mankin scoring. In conclusion, the PEA platform shows safety and efficacy upon intra-articular injection, and its extended degradation and release profiles compared to the currently used PLGA platforms may render it a good alternative. Even though further in vivo studies may need to address dosing and readout parameters such as pain, no effect on cartilage pathology was found and inflammation was effectively lowered in OA joints.
Asunto(s)
Amidas/administración & dosificación , Antiinflamatorios/administración & dosificación , Microesferas , Osteoartritis/tratamiento farmacológico , Poliésteres/administración & dosificación , Triamcinolona Acetonida/administración & dosificación , Amidas/química , Amidas/uso terapéutico , Animales , Antiinflamatorios/química , Antiinflamatorios/uso terapéutico , Células Cultivadas , Condrocitos/efectos de los fármacos , Condrocitos/metabolismo , Dinoprostona/metabolismo , Liberación de Fármacos , Femenino , Humanos , Inyecciones Intraarticulares , Articulación de la Rodilla/efectos de los fármacos , Articulación de la Rodilla/patología , Osteoartritis/patología , Poliésteres/química , Poliésteres/uso terapéutico , Ratas Sprague-Dawley , Triamcinolona Acetonida/química , Triamcinolona Acetonida/uso terapéuticoRESUMEN
In this study, we investigated the potential of celecoxib-loaded polyester amide (PEA) microspheres as an auto-regulating drug delivery system for the treatment of pain associated with knee osteoarthritis (OA). Celecoxib release from PEA microspheres and inflammation responsive release of a small molecule from PEA was investigated in vitro. Inflammation responsive release of a small molecule from PEA was observed when PEA was exposed to cell lysates obtained from a neutrophil-like Hl-60 cell line. Following a short initial burst release of ~15% of the total drug load in the first days, celecoxib was slowly released throughout a period of >80days. To investigate biocompatibility and degradation behavior in vivo, celecoxib-loaded PEA microspheres were injected in OA-induced (ACLT+pMMx) or contralateral healthy knee joints of male Lewis rats. Bioactivity of celecoxib from loaded PEA microspheres was confirmed by PGE2 measurements in total rat knee homogenates. Intra-articular biocompatibility was demonstrated histologically, where no cartilage damage or synovial thickening and necrosis were observed after intra-articular injections with PEA microspheres. Degradation of PEA microspheres was significantly higher in OA induced knees compared to contralateral healthy knee joints, while loading the PEA microspheres with celecoxib significantly inhibited degradation, indicating a drug delivery system with auto regulatory behavior. In conclusion, this study suggests the potential of celecoxib-loaded PEA microspheres to be used as a safe drug delivery system with auto regulatory behavior for treatment of pain associated with OA of the knee.