Nat Rev Rheumatol. Author manuscript; available in PMC 2015 Apr 19.
An intra-articular hip injection is the injection of a steroid (synthetic cortisone) medication into the hip joint. What is the purpose of an intra-articular hip injection? The steroid medication is a powerful anti-inflammatory medication. Pathologic changes within the hip joint (i.e. Arthritis, labral tears, etc) often lead to inflammation.
Published in final edited form as:
Intra-articular fibrocartilages. Intra-articular fibrocartilages are complete or incomplete plates of fibrocartilage that are attached to the joint capsule (the investing ligament) and that stretch across the joint cavity between a pair of conarticular surfaces. While intra-articular fractures appear very similar to those that do not involve a joint space (extra-articular fractures), intra-articular fractures are significantly more serious because they are associated with a much greater incidence of long-term complications.
Published online 2013 Nov 5. doi: 10.1038/nrrheum.2013.159
Previous studies have examined the use of the intra-articular injection in identifying various intra-articular hip pathologies. Byrd and Jones 12 demonstrated that fluoroscopically guided intra-articular hip joint injections are 90% accurate in the diagnosis of intra-articular hip pathology, including labral tears and ligamentum teres rupture. The hip joint, a diarthrodial or synovial joint, under normal conditions can function under very high loads and stresses for seven to eight decades. Synovial and intra-articular pathology may prove more contributory as our understanding of these processes evolves.
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Abstract
Diarthrodial joints are well suited to intra-articular injection, and the local delivery of therapeutics in this fashion brings several potential advantages to the treatment of a wide range of arthropathies. Possible benefits include increased bioavailability, reduced systemic exposure, fewer adverse events, and lower total drug costs. Nevertheless, intra-articular therapy is challenging because of the rapid egress of injected materials from the joint space; this elimination is true of both small molecules, which exit via synovial capillaries, and of macromolecules, which are cleared by the lymphatic system. In general, soluble materials have an intra-articular dwell time measured only in hours. Corticosteroids and hyaluronate preparations constitute the mainstay of FDA-approved intra-articular therapeutics. Recombinant proteins, autologous blood products and analgesics have also found clinical use via intra-articular delivery. Several alternative approaches, such as local delivery of cell and gene therapy, as well as the use of microparticles, liposomes, and modified drugs, are in various stages of preclinical development.
Introduction
For a drug with a direct mode of action, local administration offers several advantages over systemic delivery, including increased bioavailability, reduced systemic exposure, fewer off-target effects and adverse events, and lower total drug cost. Being discrete cavities, most diarthrodial joints are well suited to local drug delivery via intra-articular injection. Osteoarthritis (OA), which affects individual joints, and polyarticular inflammatory pathologies, including rheumatoid arthritis (RA) and gout, have high incidence and long-term therapeutic need; moreover, current treatment options are inadequate for many patients. Thus, tremendous interest has been generated in achieving successful localization of therapeutics at the pathological site, to maximize efficacy and reduce drug cost. Most common disorders of diarthrodial joints—with RA the exception—are not accompanied by clinically significant extra-articular manifestations, which makes the prospect of local therapy particularly appealing. Reflecting the growing interest in this field, the second International Symposium on Intra-Articular Treatment will be held in Barcelona in October 2013.126
This Review discusses therapeutics that can be comfortably introduced into the joint in an outpatient setting via a small-gauge needle. Arthroscopy and other surgical procedures are, therefore, excluded. First, we describe how the biology of the joint controls the entry and clearance of exogenous molecules. Next, we outline current uses of intra-articular therapy in rheumatology and orthopaedics. Finally, we consider the development of emerging strategies such as drug-delivery particles, gene transfer and cell-based therapies.
The pharmacokinetics of the joint
The joint-space ‘dwell time’ of a therapeutic agent is influenced by the rate at which the molecule reaches and is cleared from the synovial fluid. The former parameter depends on the size and route of administration of the drug, whereas the rate of efflux of a soluble agent is largely independent of these properties (Figure 1). Systemically delivered, soluble substances enter the joint space via the capillary network of the sub-synovium, which is highly vascularized; small molecules also leave via the vasculature whereas larger substances such as proteins exit via the lymphatic system.
How soluble molecules get into and out of joints. Macromolecules in the circulation enter the joint via the synovial capillaries and are sieved by the fenestrated endothelium of the capillaries (see figure 2). Small molecules also enter via the capillaries, but the major resistance to their entry is provided by the ECM of the synovial interstitum. Intra-articular injection by-passes both of these constraints to entry. However, both large and small molecules rapidly exit the joint via the lymphatics and small blood vessels, respectively
Drug delivery to cartilage
For certain indications, it is necessary to deliver therapeutics to cartilage. Because cartilage is avascular, it is inefficiently targeted by systemic delivery of drugs, which must first reach the synovial fluid and then diffuse through the cartilagenous extracellular matrix (ECM). Unless damaged, this matrix is highly anionic and increasingly impermeable to molecules much greater than the size of albumin (~67,000 Da), depending upon their charge and conformation. Intra-articular therapy improves delivery to cartilage and can thus increase therapeutic efficacy, but in doing so it exposes chondrocytes to higher concentrations of drugs. In developing intra-articular therapeutics, therefore, investigators must be aware of the potential for exposing previously unrecognized chondrotoxicity.
Joint-space entry is size-dependent
To enter the joint space from the synovial circulation, solutes need to pass through two layers of resistance in series: the capillary wall and the ECM of the synovial intima. The endothelial lining of the subsynovial capillaries is fenestrated, with the fenestrations orientated towards the joint space; this orientation facilitates the directed exit of solutes from these capillaries. Because the synovium has no basement membrane to impede molecular transit, small molecules pass freely through the vascular endothelium, and the major determinant of their entry into the joint space is their rate of diffusion through the synovial interstitium. With this entry route being dependent on the small pores of the capillary endothelium and the tight spaces of the interstitial matrix, unimpeded transport through passive diffusion occurs only for small molecular weight compounds, typically <10 kDa.
For larger molecules, the endothelial lining imposes a size-dependent sieving effect on the rate of passage (Figure 2). For example, the concentration ratio of normal synovial fluid:serum for albumin (which is 67 kDa) is ~0.40; for the much larger molecules α2–macroglobulin and IgG this ratio drops to 0.03–0.05. Fibrinogen, with a MW of 340 kDa, is rarely found in synovial fluid in the absence of inflammation, probably because of its very high Stokes radius (that is, hydrodynamic radius).
Concentration ratios of proteins between serum and synovial fluid. Entry of macromolecules into the synovial fluid from the systemic circulation is normally impeded as a function of molecular size (see also Figure 1)
Inflammation increases synovial permeability
Synovial inflammation is a key feature of many joint pathologies; most notably observed in RA and following joint injury, it is also present in OA. In an inflamed joint, capillary permeability increases, thereby enhancing the entry of macromolecules into the joint space. Evidence of this effect can be found in the protein content of synovial fluid from patients with RA, which is increased in comparison with healthy controls, as well as notable increases in the proportion of large to small molecular components in RA samples.,
Macromolecules have short dwell time
Although entry of macromolecules into joints is constrained, their removal from joints occurs via the lymphatic system in a fashion that, unlike their entry, is independent of size (Figure 1). The rate of removal of macromolecules from the joint is increased in patients with RA, reflecting enhanced drainage from the joint space due to greater synovial lymph flow.
Because lymphatic drainage is highly efficient, the intra-articular dwell time of proteins in joints is typically a few hours or less. This timescale presents obvious problems when attempting to treat chronic joint disorders with large molecules. Although intra-articular injection can circumvent the entry restrictions imposed by synovial sieving (Figure 1), it cannot avoid rapid lymphatic clearance of a therapeutic agent. The need to increase intra-articular dwell time was a major reason why local gene delivery to joints was suggested as a therapeutic strategy. Similar time constraints exist for small molecules, which rapidly diffuse from the joint via the synovial capillaries. Larsen et al. have tabulated the half-lives of various substances within the joints of experimental animals as well as within healthy and arthritic human joints. The values reported range from 0.23 h for acridine orange (MW 370 Da) to 1.23–13.1 h for albumin and 26.3 h for hyaluronic acid (MW 3×106 Da). Intra-joint half-lives of NSAIDs and soluble steroids cluster at around 1–4 h. These values illustrate the challenges facing intra-articular therapy, especially for chronic conditions.
Intra-articular injection
Pros and cons versus systemic delivery
Although various pro-drug and particle-based strategies for targeting drugs to inflamed joints through the systemic circulation are in development, intra-articular injection remains the method of choice for local therapeutic delivery. This route of administration overcomes concerns about the extent of bioavailability, unknown or uncontrollable drug dosing, the effects of drug binding to systemic molecules, and other drug modifications that can limit the efficacy of a substance administered via systemic delivery. Moreover, it eliminates many patient compliance issues.
Nevertheless, in many countries, intra-articular injections are performed almost exclusively by rheumatologists and orthopaedists; this requirement for specialist time is limiting when repetitive, serial injections are necessary. The exclusion of the general practitioner places intra-articular delivery at a logistical disadvantage compared with oral and self-administered, subcutaneous administration. However, the development of technologies such as fluoroscopy and ultrasonography to ensure accuracy could expand the use of intra-articular injection to a wider spectrum of physicians.
Clinical history
Clinical use of intra-articular injections dates back to the 1930s when formalin, glycerin, lipodol, lactic acid and petroleum jelly were among the first substances injected into patients with arthritis. Widespread and persistent use of the technique began in the 1950s when intra-articular injections of corticosteroids became common for treating patients with RA. More recently, the use of intra-articular injections has expanded greatly with the approval of therapeutics based on hyaluronate for the treatment of OA (discussed later in this manuscript).
Delivery and adverse events
Accuracy of injection is an issue, even for large, accessible joints such as the knee where as many as 50% of intended intra-articular injections by experienced physicians can end up in extra-articular locations, . Nevertheless, Simkin has argued that, because the synovial fluid is contiguous with the interstitial fluid of the synovium, any injection within the joint capsule is close enough to the target site. Accuracy is improved by fluoroscopic and ultrasound guidance techniques, and these tools are particularly valuable for treating joints, such as the hip, that are difficult to access.
Other than injection-site reactions in certain individuals, little morbidity is associated with intra-articular injection of corticosteroids or hyaluronic acid, the main concern being infection. Incidences of 1 in 3,000 to 1 in 50,000 have been reported in the literature. Although these rates are low, the increased cumulative risk of infection with repeat administration and concern about possible adverse effects of corticosteroids on cartilage create reluctance to inject joints too frequently. No rigid guidelines on this matter exist, but most practitioners are reluctant to inject a joint more than once every 3–6 months, unless delivering agents such as hyaluronic acid, which require multiple injections.
Intra-articular therapeutics
Corticosteroids
A long history of intra-articular corticosteroid use exists for patients with RA. Although the introduction of TNF antagonists has reduced the need for intra-articular corticosteroids in this disease, they are still administered to individual symptomatic joints that fail to respond to systemically delivered drugs.
Joint-space kinetics
Corticosteroids are highly hydrophobic, small (<700Da) hydrocarbons that can be transported into the joint space after systemic administration through trans-capillary diffusion, although resulting bioavailability in the synovial fluid is much reduced in comparison with the systemic compound. Thus, one motivation for developing intra-articular delivery of corticosteroids has been to increase effective dosing. Besides increasing the rate of entry to the joint, intra-articular injection also enables delivery of modified molecules that would be incompatible with systemic delivery—such modifications can increase the intra-joint retention of corticosteroid formulations. Drug clearance is thus reduced through the use of excipients (for example, polyethylene glycol, dextran or polysorbate-based suspension) that promote retention of the drug in an aqueous solution, or salts that promote retention of the steroid in a crystalline form over long periods of time. In this manner, the drugs are complexed with salts or polymers and suspended in aqueous solutions that act to sequester the drug from the synovial fluid and delay clearance from the joint space, . Nevertheless, the intra-articular half-lives achieved for corticosteroids have rarely been found to exceed 12 hours, owing to the very low molecular weights of these compounds.
Roles in rheumatology and orthopaedics
Intra-articular corticosteroids are a mainstay of therapy in OA and are typically reserved for joints with refractory pain and/or effusion. Although pain and other symptoms are reduced for up to 4 weeks following injection, there is concern that prolonged exposure to steroids might adversely affect articular cartilage and thus accelerate the progress of the disease. For this reason, many physicians limit the use of corticosteroids to 3–4 intra-articular injections annually into any given joint with OA.
Corticosteroids are also administered for gout, and for treating many other circumstances where the joint is painful or inflamed. Their use after injury to the joint to prevent the development of post-traumatic OA might also be possible; the results of a cartilage-explant study published in 2013 indicate that short-term glucocorticoid therapy might prevent the catabolic consequences of mechanical injury and proinflammatory cytokines.
Formulation and use
A number of different corticosteroid formulations are available for intra-articular injection (Box 1). Few studies have compared their effectiveness; those that have done so suggest that triamcinolone hexacetonide might be of greater benefit than other preparations in RA, juvenile idiopathic arthritis and in OA, perhaps because it is least soluble
Box 1 | Drugs approved by the FDA for intra-articular administration
Corticosteroids
- Hydrocortisone tebutate (Hydrocortone-TBA)
- Betamethasone acetate;betamethasone sodium phosphate (Celestone Soluspan)
- Methylprednisone acetate (Depo-Medrol)
- Triamcinolone acetonide (Kenalog-40)
- Triamcinolone diacetate (Aristocort Forte)
- Triamcinolone hexacetonide (Aristospan)
- Dexamethasone sodium phosphate
Hyaluronic acids
- Synvisc
- Synvisc-one*
- Hyalgan
- Supartz
- OrthoVisc
- Euflexxa (previously Nuflexxa)
- Gel-One*
*These products are crosslinked preparations and are delivered as a single intra-articular injection; others require 3–5 doses
Various analgesics
Several studies have suggested that intra-articular glucocorticoid injection for knee synovitis has a better outcome in resting patients than in mobile patients. Nevertheless, on the basis of objective measures of serum levels of triamcinolone hexacetonide, cortisol and adrenocorticotropic hormone, immobilization does not seem to retard glucocorticoid resorption after intra-articular administration.
Hyaluronate
Intra-articular administration of the ECM component hyaluronate is very common for the treatment of pain in joints with OA that has not responded to NSAIDs or analgesics such as acetaminophen. Seven different hyaluronate preparations have been approved by the FDA for injection into the knee (Box 1); a growing literature also investigates their use in other joints such as the hip, shoulder, facet joint and the small joints of the hands and feet.
Joint-space kinetics
Unmodified hyaluronate reportedly resides within the joint space for 12–24 h following intra-articular delivery. Historically presumed to be the main lubricant of the joint hyaluronate is believed to act as a viscosupplement following intra-articular injection, replacing or supplementing the endogenous molecule. As such, its longevity and persistence within the joint space are crucial to its function, which depends on its physical presence. Thus, investigators are developing very high molecular weight, or crosslinked, hyaluronate preparations that can reportedly contribute to intra-articular half-lives exceeding 48 h in animal studies; crosslinked preparations are also in clinical use (Box 1).
Clinical performance and development
Given the frequency of OA and the current lack of disease-modifying therapies, intra-articular injections of hyaluronate are widely used and represent one of the most common reasons for intra-articular injection. However, opinion remains divided on their efficacy and considerable divergence is reported in the literature, including in the contrasting results of meta-analyses., Potentially, improved understanding of how ECM molecules such as hyaluronate influence the intra-articular pathophysiology of the joint in OA will lead to more effective alternatives. Indeed, interest is high in the possible intra-articular application of another lubricating macromolecule, lubricin, for the treatment of OA. Lubricin, also known as proteoglycan 4, is thought to be particularly important for cartilage-on-cartilage lubrication and to be more effective than hyaluronic acid in this regard. Its absence in humans with the disease camptodactylyl-arthropathy-coxavara-pericarditis syndrome or knock-out mice leads to cartilage degeneration. Intra-articular injection of lubricin prevents the development of post-traumatic OA in rats.
Biologic agents
Joint-space kinetics of proteins
The success of infliximab, etanercept, adalimubab and other anti-TNF agents as systemic treatments for RA has led to their intra-articular use in individual joints that do not respond to systemic therapy. Other recombinant proteins, such as the IL-1 receptor antagonist anakinra and the anti-IL-1β monoclonal antibody canakinumab have followed suit and are being trialled as joint injections (Table 1). These agents are typically soluble proteins of with kinetics of joint clearance that, in line with the discussion in the “Pharmokinetics of the joint” section, can be expected to be approximately 2–4 h.
Table 1
Trials of recombinant proteins and synthesized peptides delivered by intra-articular injection
Study name; ClinicalTrials.gov identifier | Drug* and comparator | Indication | Study phase; design | Current status; results reported‡ |
---|---|---|---|---|
Intra-Articular Injection of Etanercept in Patient Suffering From Rheumatoid Arthritis: a Double-Blind Randomized Study; NCT0052218498 | Etanercept vs steroid | RA | Phase III; Double-blind RCT | Completed Nov 2006; no results reported |
Evaluation of The Efficacy And Safety of Intra-Articular Etanercept in Patients With Refractory Knee Joint Synovitis; NCT0067878299 | Etanercept vs placebo | Refractory knee-joint synovitis: RA, PsA and SpA | Phase II; single-blind RCT | Completed Dec 2007; no results posted (associated biomarker study published100) |
Intraarticular Injection of Infliximab; NCT00521963101 | Infliximab vs corticosteroid | Monoarthritis of the knee, or residual knee inflammation in controlled polyarthritis | Phase II/III; double-blind RCT | Recruitment status unknown, last update Aug 2007 |
Seronegative Oligoarthritis of the Knee Study (SOKS); NCT01216631102 | IA vs IV infliximab vs methylprednisolone | SpA | Phase II; double-blind RCT | Recruitment status unknown, no updates since record created in 2010 |
Treatment Of Knee Osteoarthritis With Intra-Articular Infliximab; NCT01144143103 | Infliximab vs methylprednisolone vs placebo | Knee OA | Phase IV; double-blind RCT | Completed Dec 2010; no results posted |
Study of Intra-articular DLX105 Applied to Patients With Severely Painful Osteoarthritis of the Knee; NCT00819572104 | DLX105§ vs placebo | Severely painful knee OA | Phase I/IIa; double-blind RCT | Completed Sep 2010; no results posted |
Study to Prevent Cartilage Damage Following Acute Knee Injury; NCT00332254105 | Anakinra vs placebo | Severe knee injury | Phase I/II; double-blind RCT | Completed Jun 2007; temporary improvement in KOOS score46 |
Treatment for Patients With Osteoarthritis (OA) of the Knee; NCT00110916106 | Anakinra vs placebo | Painful knee OA | Phase II; double-blind RCT | Completed Feb 2005; results published (anakinra not better than placebo)44 |
To Determine the Safety, Tolerability, Pharmacokinetics and Effect on Pain of a Single Intra-articular Administration of Canakinumab in Patients With Osteoarthritis in the Knee; NCT01160822107 | Canakinumab vs placebo injection, with or without oral naproxen vs oral placebo | Mild-to-moderate knee OA | Phase II; double-blind RCT | Completed; raw results posted Sep 2012, no analysis available |
A Phase 1, Double-Blind, Randomized, Single Dose Escalation Safety Study of Intra-articular OP-1 in Subjects With Osteoarthritis of the Knee (Knee OA); NCT0045615747 | BMP7 vs placebo | Knee OA | Phase I; double-blind RCT | Completed; results published (support continued development)48 |
Double-Blind, Randomized, Single Dose Escalation Safety Study of Intraarticular Bone Morphogenic Protein (38A BMP-7) in Subjects With Osteoarthritis (OA) of the Knee; NCT01133613108 | BMP7 vs placebo | Knee OA | Phase I; double-blind RCT | Completed Oct 2011; no results posted |
Dose Finding Study of Bone Morphogenetic Protein 7 (BMP-7) in Subjects With Osteoarthritis (OA) of the Knee; NCT0111104549 | BMP7 vs placebo | Knee OA | Phase II; double-blind RCT | Completed Aug 2011; no results posted |
AS902330 in Cartilage Injury Repair (CIR); NCT01066871109 | FGF18 vs placebo | Acute injury of knee cartilage | Phase II; double-blind RCT | Ongoing, recruitment ended, no estimated completion date |
Study of AS902330 (rhFGF-18) Administered Intra-articularly in Patients With Knee Primary Osteoarthritis Who Are Candidates for Total Knee Replacement; NCT00911469110 | FGF18 vs placebo | Knee OA eligible for TJR | Phase I; double-blind RCT | Completed Jun 2010; no results posted |
A Multicenter Study of rhFGF 18 in Patients With Knee Osteoarthritis Not Requiring Surgery; NCT01033994111 | FGF18 vs placebo | Knee OA not requiring surgery | Phase I; double-blind RCT | Data collection completed; no results posted |
A Study to Investigate the Safety and Effectiveness of Different Doses of Sprifermin (AS902330) in Patients With Osteoarthritis of the Knee (FORWARD); NCT01919164112 | FGF18 vs placebo | Knee OA | Phase II; double-blind RCT | Recruiting patients |
A Multicenter trial of AS902330 (Recombinant Human Fibroblast Growth Factor-18) or Placebo After Microfracture Surgery for Cartilage Injury of the Knee; NCT01689337113 | FGF18 vs placebo | Microfracture of the femoral articular surfaces with intact subchondral bone | Phase II; double-blind RCT | Recruiting patients |
Efficacy and Safety Study of Intra-articular Multiple Doses of Icatibant in Patients With Painful Knee Osteoarthritis; NCT00303056114 | Icatibant‖ vs placebo | Knee OA | Phase II; double-blind RCT | Completed Jul 2007; no results posted |
‡As of September 2013.
§DLX105 is a single-chain antibody fragment anti-TNF agent.
‖Icatibant is a chemically-synthesized 10-amino acid peptide antagonist of bradykinin B2 receptors.
Abbreviations: ACL, anterior cruciate ligament; BMP7, bone morphogenic protein 7 (also known as osteogenic protein 1); FGF18, fibroblast growth factor 18; IA, intra-articular; IV, intravenous; KOOS, knee injury and osteoarthritis outcome score; OA, osteoarthritis; PsA, psoriatic arthritis; RA, rheumatoid arthritis; RCT, randomized controlled trial; SpA, spondyloarthritis; TJR, total joint replacement.
Systemic vs intra-articular anti-TNF agents
Clinical trials of joint injections of the TNF antagonist etanercept have been pursued for the treatment of both RA and refractory knee joint synovitis (Table 1). Similarly, intra-articular delivery of infliximab for the treatment of OA and spondyloarthritis has been compared with intravenous delivery of the biologic agent or corticosteroid. Although no randomized controlled trial has been performed, anecdotal reports indicate outcomes of success in treating spondyloarthritis, RA and OA.– However, intra-articular delivery of proteinaceous anti-TNF agents has not become a mainstay of clinical care.
Clinical progress with other proteins
Recombinant interleukin-1 receptor antagonist (rIL-1Ra; anakinra) has been evaluated as an intra-articular treatment for OA. Despite the encouraging results of an open-label pilot study, a subsequent phase II study showed only short-term benefit. This finding might reflect the rapid egress of rIL-1Ra, a 17 kDa protein, from the joint. Nevertheless, a single, intra-articular injection of anakinra immediately after injury prevented post-traumatic OA in a mouse fracture model of the disease.38 Of interest, the same dose administered daily for 1 month by subcutaneous osmotic pump had no effect. In a phase I clinical study, intra-articular injection of anakinra improved short-term outcomes after rupture of the anterior cruciate ligament. As for TNF antagonists and any new indication, the time, amount and dosing to achieve a therapeutic concentration in the joint space, albeit for a short duration, are critical but unknown variables.
Intra-articular delivery of bone morphogenetic protein 7 (BMP7) showed promising results in a phase I clinical study in patients with OA of the knee, but data from the subsequent phase II trial have not yet been published.97 Fibroblast growth factor 18 (FGF18) and canakinumab are also in current clinical trials testing their efficacy as intra-articular treatments for OA (Table 1).
Autologous blood products
Platelet-rich plasma (PRP) is widely used by the orthopaedic community as a treatment for a variety of musculoskeletal problems, including OA, despite scant solid evidence to commend this approach. A few case reports and small clinical series in which PRP has been injected into joints with OA have been published; however, the results are equivocal and much more research is needed. Clinical experiences are difficult to compare, because different preparations of PRP have different compositions and variable effects on inflammation. A concentrated PRP product known as Autologous Protein Solution is being evaluated in patients with OA.
Autologous conditioned serum is obtained from incubated blood and injected into joints with OA or other painful conditions. Whole blood is incubated with medical-grade, etched glass beads that induce the synthesis of anti-inflammatory molecules, including IL-1Ra. After filtration, the conditioned serum is injected into the joint. Apart from rare cases of acute inflammation after intra-articular administration of this complex preparation, the overall incidence of complications seems to be low. A randomized controlled clinical trial in 376 patients with knee OA demonstrated a therapeutic effect superior to that achieved with the injection of saline or hyaluronic acid.
Analgesics
Local anaesthetics have FDA approval as injections for the production of local or regional anaesthesia or analgesia. Intra-articular analgesia is often used after joint surgery and occasionally in joints with OA. Lidocaine, bupivacaine, ropivacaine, opiates and have been evaluated as intra-articular analgesics, mostly for post-operative pain, Botulinum toxin A has been evaluated as a therapy for chronic joint pain and OA Chondrolysis associated with the use of intra-articular local anaesthetic ‘pain pumps’ has been described by several groups,– which has raised concern about the clinical use of intra-articular anaesthetics. Dose-dependent toxic effects of analgesics, including apoptosis, have been demonstrated in vitro. The type and concentration of anaesthetic, as well as additives and pH, have been implicated in the chondrotoxicity of intra-articular analgesics., Ropivocaine is less toxic in cultured chondrocytes and cartilage explant systems than bupivacaine.
Intra-articular drug delivery systems
As we have mentioned, low molecular weight compounds are cleared rapidly from the joint space. Furthermore, poor drug solubility and poor tissue distribution within the joint have helped to create interest in designing drug delivery systems specifically for the intra-articular environment. As we discuss here, liposomes and microparticles have consequently been evaluated in the context of intra-articular drug delivery.
Liposomes
Liposomes entrap primarily hydrophobic drugs in a lipid bilayer or lipid phase, and provide for sustained release through liposome dissolution and slow solubilization of the drug. Liposome drug-loading efficiencies as high as 90% are possible for many hydrophobic drugs and these vesicles are thus attractive for delivering corticosteroids such as triamcinolone, celocoxib, dexamethasone, and cortisol-21-palmitate.– The longevity of the drug and its onset of action are dependent upon particle size, with results suggesting that liposomes can extend drug activity by as much as 14 days. This pharmacodynamic extension might be attributable to efficient endocytosis of the liposome and/or to prolonged drug re-solubilization. Particle sizes of 100 nm–5 µm seem to be suitable for achieving prolonged drug retention, with too rapid clearance of drug from liposomes noted for much smaller particles.,
Liposomes are less useful with more polar drugs, such as methotrexate, because of low drug loading ratios and a rapid burst release encountered in the aqueous environment of the synovial fluid., Moreover, liposomal preparations require mixing of the drug with organic solvents that are damaging to proteinaceous drugs. Nevertheless, several therapeutic liposomal formulations are in clinical use for a variety of indications, including the delivery of doxorubicin in cancer (for example, Doxil™, Janssen Biotech), amphotericin for fungal infection (for example, AmBisome™, Astellas Pharma) and cytarabine for cancer (Depocyt®, Sigma-tau Pharma), with good safety profiles that suggest their potential utility for localized intra-articular delivery. Knowledge of these liposomal formulations applies, however, to intravenous, topical or intramuscular use, with only one liposomal product available for intra-articular delivery, a palmitylated dexamethasone, and only in Germany (Lipotalon®, Merckle).
Microparticles and nanoparticles
For proteinaceous drugs and polar molecules, synthetic polymeric microparticles and nanoparticles might be more suitable than liposomes as drug delivery systems for the joint space. Biodegradable microparticles composed of polyesters (for example, PGLA, PLLA), polyanhydrides, and polycaprolactones have been developed for broader clinical applications, including the encapsulation of synthetic hormones (Lupron®, Abbott), tretinoin (RetinA Micro®, OrthoNeutrogena) and risperidone (Riseperdal®, Janssen Pharma) and have shown potential for prolonging intra-articular drug residence time in preclinical studies. For betamethasone,, methotrexate, diclofenac, siRNA and paclitaxel, for example, encapsulation in microspheres composed of PLLA, PLGA, or polycaprolactones contributed to a sustained release effect in animal models of arthritis that could be observed up to 21 days after delivery in some cases.–
Drug availability within the joint space following delivery within a microsphere depends on the competing and synergistic processes of drug diffusion from the polymer, erosion of the polymeric microparticle, and size-dependent endocytosis of the particle. As with liposomes, microparticles of a range of sizes can seemingly be endocytosed without provoking deleterious inflammation (generally particles <30 mm), and a lower size limit exists below which little benefit of particulation is noted (50 nm). Drugs have also been studied following encapsulation in naturally derived polymeric materials, including chitosan microspheres, albumin, gelatin, elastin-based systems and collagen. Overall, particle-based delivery systems have the potential to increase drug residence times greatly, with 10–30-fold increases reported in pre-clinical models. A clinical study reported in 2013 of a PGLA-encapsulated corticosteroid, triamcinolone acetonide (FX006, Flexion Therapeutics), demonstrated residence in the joint space at therapeutic concentrations at 6 weeks after injection,137 providing some evidence of even longer periods of sustained release for microcapsules. Nevertheless, no particle-based or liposome drug-delivery system has yet advanced past clinical trials for intra-articular drug delivery in the USA, possibly because of the need to establish cost-effective manufacturing processes and dosing strategies.
Modifying drugs to increase dwell time
Direct modification of known drugs is a widely used strategy to prolong their residence time in the joint. Conjugation of a polyethylene glycol (PEG) moiety to a drug—PEGylation—is a frequently used method to increase the bioavailability of hydrophobic drugs and increase their molecular weight towards the goal of delaying systemic elimination. Similarly, a thermally responsive small polypeptide, elastin-like polypeptide (ELP), has been conjugated to protein drugs in a process called ELPylation. ELPylation leads to the temperature-controlled formation of a drug depot at the site of injection that has the potential to decrease drug clearance from the injection site. ELP has been conjugated to multiple drugs including TNF and IL-1 antagonists, for application to intra-articular or perineural delivery. This approach has the potential to provide a 20-fold increase in intra-articular drug residence time, but is complicated by involving the creation of a novel conjugate, rather than an entrapped drug, with pharmacokinetics and pharmacodynamics that are not thoroughly studied.
Nonsurgical synovectomy with radionuclides
When particles of phagocytosable size are injected into joints they are taken up by macrophages present in the synovium. This process has been used to achieve nonsurgical synovectomy via the incorporation of radioactive materials in small particles, suspensions of which are injected into the joint. The technique is used for chronic synovial conditions, such as diffuse pigmented villonodular synovitis and the haemorthrosis of patients with haemophilia, that are difficult to treat by other means. Historically a common treatment for RA, radioactive synovectomy has also been evaluated in OA. Improvements in pain and inflammation were noted, with the greatest effects seen in knees with the least radiologic evidence of damage. Isotopes of the lanthanide series of elements, such as Y90, Sm153, Er169 and Yb175, are particularly suited to this purpose and their use has supplanted chemical synovectomy as the nonsurgical method of choice. Although radiation synovectomy is rarely used for OA or RA, it is a method of choice for haemophilic synovitis. Radiation synovectomy is complicated by rare cutaneous radiation necrosis and concerns about genotoxic effects.
Gene therapy
Local gene transfer to the joint provides one solution to the problem of maintaining a sustained, therapeutic concentration of a gene product within a diseased joint, and can be accomplished by administration of cells genetically modified ex vivo or by the direct, intra-articular injection of viral or non-viral vectors. Intra-articular gene therapy—as reviewed in this journal in 2011—has been evaluated in phase I clinical trials in patients with RA and OA. A phase II study in RA, using adeno-associated virus to deliver etanercept, was marred by the death of one of the study subjects but was allowed to proceed to completion. Phase II trials in OA, using allogeneic cells expressing transforming growth factor β1, are continuing in Korea and the USA.
Cell-based therapies
The first clinical use of intra-articular cell delivery was in the context of gene therapy, using genetically modified, autologous synovial fibroblasts (Table 2). Since then, chondrocytes and blood cells have been injected into human joints (Table 2), but by far the greatest activity surrounds the use of mesenchymal stem cells (MSCs). Their use has increased spectacularly in the past 3 years: 31trials are listed in Table 2; 23 of them involve MSCs and, of these, 20 were registered on ClinicalTrials.gov from 2010 onwards.
Table 2
Clinical trials involving the intra-articular injection of cells
Study name; ClinicalTrials.gov identifier | Cell type and source | Indication | Study phase; design | Current status;* results reported |
---|---|---|---|---|
Clinical Trial to Assess the Safety, Feasibility, and Efficacy of Transferring a Potentially Anti-arthritic Cytokine Gene to Human Joints with Rheumatoid Arthritis; NIH OBA number: 9406 074‡ | Autologous synovial cells (transduced to express IL-1Ra) | RA | Phase I; open label | Completed; results published84 |
Safety Study of TissueGene-C in Degenerative Joint Disease of the Knee (TGC-03-01); NCT00599248115 | Chondrocyte, allogeneic (transduced to express TGF-β1) | Knee OA scheduled for TKA | Phase I; single-blind RCT | Completed May 2010; results published116 |
Study of TG-C in Patients With Grade 3 Degenerative Joint Disease of the Knee; NCT01221441117 | Chondrocyte, allogeneic (transduced to express TGF-β1) | Knee OA, KLG III | Phase II; double-blind RCT | Ongoing, recruitment ended, estimated completion date Oct 2014 |
Efficacy and Safety Study of TissueGene-C to Degenerative Arthritis; NCT01671072118 | Chondrocyte, allogeneic (transduced to express TGF-β1) | Knee OA, KLG II–III | Phase II; single-blind RCT | Completed Jan 2013; abstract published119 |
Autologous Chondrocyte Intra-articular Implantation in Patients With Severe Hip Osteoarthritis; NCT01500811120 | Chondrocyte, autologous | Severe hip OA | Phase I; open label | Unknown; estimated completion date Aug 2013 |
Articular Cartilage Resurfacing With Mesenchymal Stem Cells In Osteoarthritis Of Knee Joint; NCT01207661121 | MSC, autologous (source unspecified) | Knee OA | Phase I; open label | Completed Nov 2010; no results posted |
Adult Stem Cell Therapy for Repairing Articular Cartilage in Gonarthrosis; NCT01227694122 | MSC, autologous, bone-marrow-derived | Knee OA | Phase I/II; open label | Study completed; no study results posted |
Side Effects of Autologous Mesenchymal Stem Cell Transplantation in Ankle Joint Osteoarthritis; NCT01436058123 | MSC, autologous, bone-marrow-derived | Ankle joint OA | Phase I; open label | Completed Sep 2011; no results posted |
Stem Cell Transplantation for the Treatment of Knee Osteoarthritis; NCT00550524124 | MSC, autologous, bone-marrow-derived | Knee OA | Phase I; open label | Recruiting by invitation |
Intra-Articular Autologous Bone Marrow Mesenchymal Stem Cells Transplantation to Treat Mild to Moderate Osteoarthritis; NCT01459640125 | MSC, autologous, bone-marrow-derived | Mild-to-moderate knee OA | Phase II; open label, active comparator: hyaluronic acid | Recruiting, estimated completion date Mar 2014 |
Safety and Efficacy of Autologous Bone Marrow Stem Cells for Treating Osteoarthritis; NCT01152125126 | MSC, autologous, bone-marrow-derived | OA, KLG III–IV | Phase I/II; open label | Recruiting by invitation, estimated completion date Jan 2012 |
Treatment of Knee Osteoarthritis With Autologous Mesenchymal Stem Cells (KDD&MSV); NCT01183728127 | MSC, autologous, bone-marrow-derived | Knee OA, KLG II–IV | Phase I/II; open label | Ongoing, recruitment over, estimated completion date Jun 2013 |
Mesenchymal Stem Cell Transplantation in Osteoarthritis of Hip Joint; NCT01499056128 | MSC, autologous, bone-marrow derived | Hip OA | Phase I; open label | Completed Mar 2011; no results posted |
The Effects of Intra-articular Injection of Mesenchymal Stem Cells in Knee Joint Osteoarthritis; NCT01504464129 | MSC, autologous, bone-marrow-derived | Knee OA | Phase II; double-blind RCT | Completed Nov 2012; no results posted |
Allogeneic Mesenchymal Stem Cells in Osteoarthritis; NCT01453738130 | MSC, allogeneic, source unspecified | Knee OA | Phase II; double-blind RCT | Ongoing, recruitment over, estimated completion date Jul 2014 |
Allogeneic Mesenchymal Stem Cells for Osteoarthritis; NCT01448434131 | MSC, allogeneic, source unspecified | Knee OA | Phase II; double-blind RCT | Ongoing, recruitment over, estimated completion date Feb 2013 |
Treatment of Knee Osteoarthritis With Allogenic Mesenchymal Stem Cells (MSV_allo); NCT01586312132 | MSC, allogeneic, bone-marrow-derived | Knee OA | Phase II; double-blind RCT, active comparator: hyaluronic acid | Active, recruiting; estimated completion date Dec 2013 |
A Phase I/II Study of Chondrogen Delivered by Intra-Articular Injection Following Meniscectomy; NCT00225095133 | MSC, allogeneic, source unspecified | Meniscectomy | Phase I/II; double-blind; randomized | Completed; no results posted |
Follow-up Study of Chondrogen®Delivered by Intra-Articular Injection Following Meniscectomy; NCT00702741134 | MSC, allogeneic, source unspecified | Partial medial menisectomy | Phase II; double-blind RCT | Recruitment status unknown, last update Aug 2010 |
Safety and Efficacy Study of MSB-CAR001 in Subjects 6 Weeks Post an Anterior Cruciate Ligament Reconstruction; NCT01088191135 | MSC, allogeneic, source unspecified | ACL reconstruction | Phase I/II; double-blind RCT, active control: hyaluronan | Ongoing, recruitment over, estimated completion date Jun 2014 |
Autologous Adipose Tissue Derived Mesenchymal Stem Cells Transplantation in Patients With Degenerative Arthritis; NCT01300598136 | MSC, autologous, adipose-tissue derived | Knee OA | Phase I/II; open label | Completed Mar 2012; no results posted |
ADIPOA - Clinical Study; NCT01585857137 | MSC, autologous, adipose-tissue-derived | Knee OA, moderate or severe | Phase I; open label | Active, recruiting; estimated completion date Apr 2015 |
Autologous Adipose-Derived Stromal Cells Delivered Intra-articularly in Patients With Osteoarthritis; NCT01739504138 | MSC, autologous, adipose-tissue-derived | OA | Phase I/II; open label | Active, recruiting; estimated completion date Dec 2015 |
Outcomes Data of Bone Marrow Stem Cells to Treat Hip and Knee Osteoarthritis; NCT01601951139 | Bone-marrow concentrate, autologous | Hip and knee OA | Phase unspecified; prospective, observational | Ongoing, not recruiting, no estimated completion date |
Autologous Stem Cells in Osteoarthritis; NCT01485198140 | Haematopoietic stem cells, autologous | Knee OA, KLG II–III | Phase I; open label | Active, recruiting; estimated completion date Aug 2013 |
Peripheral Blood-drived Stem Cell Trial on Damaged Knee Cartilage (PBSC); NCT01076673141 | Peripheral blood stem cells (identity unspecified) | Damaged articular cartilage | Phase unspecified; open label | Recruitment status unknown, last update Jul 2011 |
Allogeneic Mesenchymal Stem Cells in Osteoarthritis; NCT01453738142 | MSC, source unspecified, allogeneic | Knee OA, KLG II–III | Phase II; double blind | Ongoing, not recruiting, estimated completion date July 2014 |
Autologous Adipose Tissue Derived Mesenchymal Progenitor Cells Therapy for Patients With Knee Osteoarthritis; NCT01809769143 | Mesenchymal progenitor cells, autologous, adipose-tissue-derived | Knee OA | Phase I/II; double blind | Ongoing, not recruiting, estimated completion date October 2013 |
Autologous Bone Marrow Mesenchymal Stem Cells Transplantation for Articular Cartilage Defects Repair; NCT01895413144 | MSC, bone marrow, autologous | Knee OA | Phase I/II; open label | Recruiting |
Transplantation of Bone Marrow Derived mesenchymal Stem Cells in Affected Knee Osteoarthritis by Rheumatoid Arthritis (sic); NCT01873625145 | MSC, bone marrow, not stated whether autologous or allogeneic. | Knee OA | Phase II/III; randomized, open-label | Completed; no results posted |
Safety and Efficacy Study of MSB-CAR001 in Subjects 6 Weeks Post an Anterior Cruciate Ligament Reconstruction; NCT01088191146 | MSC, source unspecified | Knee, ACL injury | Phase I/II; double blind RCT | Ongoing, not recruiting. Estimated completion date, June 2014 |
‡This trial predates ClinicalTrials.gov and thus lacks an NCT number.
Abbreviations: ACL, anterior cruciate ligament; KLG, Kellgren–Lawrence grade; MSC, mesenchymal stem cell; OA, osteoarthritis; RCT, randomized controlled trial; TGF-β1, transforming growth factor β1; TKA, total knee arthroplasty.
As described by Barry and Murphy in this journal, the potential intra-articular use of MSCs in treating OA has attracted considerable attention because MSCs are thought to be anti-inflammatory and immunosuppressive mediators of tissue regeneration.– Encouraging preclinical data have emerged– in relation to preventing post-traumatic OA, regenerating damaged cartilaginous surfaces and reducing pain. The intra-articular injection of MSCs derived from bone marrow or fat is widely used in equine medicine for the treatment of OA and such therapies are commercially available for use in animals. Only a few small human clinical case series have been published, such as a study using autologous MSCs in four people with knee OA, with equivocal results. The immunosuppressive nature of MSCs introduces the possibility that they can be successfully allografted, which raises the prospect of developing a therapy from a universal donor; such a step would reduce the cost and complexity of generating approved treatments.
Conclusions
The intra-articular injection of therapeutic agents is an attractive strategy for the local treatment of joint diseases. Most joints are accessible to accurate injection, especially when using image guidance. Given that such injections cannot be administered too frequently, it is preferable to use reagents that have a lasting therapeutic effect. However, soluble agents are rapidly cleared from joints, regardless of the size of the drug, and this transience remains a major barrier to successful therapy. Intra-articular injection became popular in the latter half of the twentieth century owing to the introduction of intra-articular corticosteroids. Today, this treatment and the injection of hyaluronate into joints with OA form the major uses of this technique. Interest in delivering recombinant proteins, autologous blood products, particles, cells and gene therapy vectors to diseased joints continues to mount. Local delivery in this fashion is potentially safer, less expensive and more effective than parenteral delivery. Reducing the need for burdensome repeated injections of soluble therapeutics will, however, require better drug formulations with more lasting efficacy.
- Getting therapeutics into joints in a targeted and sustained fashion is difficult
- Intra-articular injection solves the delivery problem and brings several additional advantages over systemic administration, including increased bioavailability, reduced systemic exposure, fewer off-target effects and lower costs
- Soluble drugs exit joints very rapidly via the capillaries (in the case of small molecules) and lymphatic system (for macromolecules)
- Strategies for extending the intra-articular half-lives of therapeutics include the use of small particles, drug modification, and gene transfer
- Delivery of hyaluronate and corticosteroids accounts for the majority of intra-articular injections; additional therapeutics include recombinant proteins, autologous blood products and analgesics
- Clinical trials involving the intra-articular injection of mesenchymal stem cells have multiplied enormously in recent years
PubMed served as the primary database, initially using the search terms “intra-articular and therapy”. No year limitations were imposed. The list of articles was screened by title for articles in English, with a bias towards articles that were recent, clinical and novel. Non-clinical articles were included if they provided mechanistic insight or supplied pre-clinical advances. The abstracts of the selected articles were then read to identify relevant papers that were down-loaded and studied in detail. More focused searches were then conducted using search terms “intra-articular and steroid”, “intra-articular and hyaluronan”, “intra-articular and protein”, “intra-articular and cell” and “intra-articular and osteoarthritis and therapy”. Because the authors do research in the area of intraarticular therapy, they were able to identify additional references from their working knowledge of the field. ClinicalTrials.gov was searched to provide the information given in Tables 1 and and22.
Acknowledgements
The authors would like to acknowledge financial support from NIAMS in the form of the following grants: P01AR050245, R01AR047442, R01AR051085, X01 NS066865.
Footnotes
Competing interests
C. H. Evans declares that he acts as a consultant for TissueGene Inc. and holds stock in Orthogen AG. L. A. Setton declares that she holds stock in PhaseBio. V. B. Kraus declares that she has received Royalties from PhaseBio.
(NB, statement provided in online manuscript tracking system says: “CHE: Board of Directors, Orthogen AG Scientific Advisory Board, TissueGene Inc. LAS: Holds stock in PhaseBio VBK: Has received royalties from PhaseBio I need to ask VBK and LAS”).
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(Redirected from Intra-articular)
Joint | |
---|---|
Depiction of an intervertebral disc, a cartilaginous joint | |
Details | |
System | Musculoskeletal system Articular system |
Identifiers | |
Latin | Articulus Junctura Articulatio |
MeSH | D007596 |
TA | A03.0.00.000 |
FMA | 7490 |
Anatomical terminology |
A joint or articulation (or articular surface) is the connection made between bones in the body which link the skeletal system into a functional whole.[1][2][3] They are constructed to allow for different degrees and types of movement. Some joints, such as the knee, elbow, and shoulder, are self-lubricating, almost frictionless, and are able to withstand compression and maintain heavy loads while still executing smooth and precise movements.[3] Other joints such as sutures between the bones of the skull permit very little movement (only during birth) in order to protect the brain and the sense organs.[3] The connection between a tooth and the jawbone is also called a joint, and is described as a fibrous joint known as a gomphosis. Joints are classified both structurally and functionally.[4]
- 1Classification
- 3History
Classification[edit]
Joints are mainly classified structurally and functionally. Structural classification is determined by how the bones connect to each other, while functional classification is determined by the degree of movement between the articulating bones. In practice, there is significant overlap between the two types of classifications.
Clinical, numerical classification[edit]
- monoarticular – concerning one joint
- oligoarticular or pauciarticular – concerning 2–4 joints
- polyarticular – concerning 5 or more joints
Structural classification (binding tissue)[edit]
Types of joints based upon their structure (L to R): Cartilaginous joint, Fibrous joint, and Synovial joint.
Structural classification names and divides joints according to the type of binding tissue that connects the bones to each other.[1] There are four structural classifications of joints:[5]
- fibrous joint – joined by dense regular connective tissue that is rich in collagen fibers[6]
- cartilaginous joint – joined by cartilage. There are two types: primary cartilaginous joints composed of hyaline cartilage, and secondary cartilaginous joints composed of hyaline cartilage covering the articular surfaces of the involved bones with fibrocartilage connecting them.
- synovial joint – not directly joined – the bones have a synovial cavity and are united by the dense irregular connective tissue that forms the articular capsule that is normally associated with accessory ligaments.[6]
- facet joint – joint between two articular processes between two vertebrae.[7][8]
Functional classification (movement)[edit]
Joints can also be classified functionally according to the type and degree of movement they allow:[1][9] Joint movements are described with reference to the basic anatomical planes.[3]
- synarthrosis – permits little or no mobility. Most synarthrosis joints are fibrous joints (e.g., skull sutures).
- amphiarthrosis – permits slight mobility. Most amphiarthrosis joints are cartilaginous joints (e.g., intervertebral discs).
- synovial joint (also known as a diarthrosis) – freely movable.[1][9] Synovial joints can in turn be classified into six groups according to the type of movement they allow: plane joint, ball and socket joint, hinge joint, pivot joint,[10][11]condyloid joint and saddle joint.[12]
Joints can also be classified, according to the number of axes of movement they allow, into nonaxial (gliding, as between the proximal ends of the ulna and radius), monoaxial (uniaxial), biaxial and multiaxial.[13] Another classification is according to the degrees of freedom allowed, and distinguished between joints with one, two or three degrees of freedom.[13] A further classification is according to the number and shapes of the articular surfaces: flat, concave and convex surfaces.[13] Types of articular surfaces include trochlear surfaces.[14]
Biomechanical classification[edit]
Joints can also be classified based on their anatomy or on their biomechanical properties. According to the anatomic classification, joints are subdivided into simple and compound, depending on the number of bones involved, and into complex and combination joints:[15]
- Simple joint: two articulation surfaces (e.g. shoulder joint, hip joint)
- Compound joint: three or more articulation surfaces (e.g. radiocarpal joint)
- Complex joint: two or more articulation surfaces and an articular disc or meniscus (e.g. knee joint)
Anatomical[edit]
The joints may be classified anatomically into the following groups:
Unmyelinated nerve fibers are abundant in joint capsules and ligaments as well as in the outer part of intraarticular menisci. These nerve fibers are responsible for pain perception when a joint is strained.[16]
Clinical significance[edit]
Damaging the cartilage of joints (articular cartilage) or the bones and muscles that stabilize the joints can lead to joint dislocations and osteoarthritis. Swimming is a great way to exercise the joints with minimal damage.[3]
A joint disorder is termed arthropathy, and when involving inflammation of one or more joints the disorder is called arthritis. Most joint disorders involve arthritis, but joint damage by external physical trauma is typically not termed arthritis.
Arthropathies are called polyarticular (multiarticular) when involving many joints and monoarticular when involving only a single joint.
Arthritis is the leading cause of disability in people over the age of 55. There are many different forms of arthritis, each of which has a different cause. The most common form of arthritis, osteoarthritis (also known as degenerative joint disease), occurs following trauma to the joint, following an infection of the joint or simply as a result of aging and the deterioration of articular cartilage. Furthermore, there is emerging evidence that abnormal anatomy may contribute to early development of osteoarthritis. Other forms of arthritis are rheumatoid arthritis and psoriatic arthritis, which are autoimmune diseases in which the body is attacking itself. Septic arthritis is caused by joint infection. Gouty arthritis is caused by deposition of uric acid crystals in the joint that results in subsequent inflammation. Additionally, there is a less common form of gout that is caused by the formation of rhomboidal-shaped crystals of calcium pyrophosphate. This form of gout is known as pseudogout.
Temporomandibular joint syndrome (TMJ) involves the jaw joints and can cause facial pain, clicking sounds in the jaw, or limitation of jaw movement, to name a few symptoms. It is caused by psychological tension and misalignment of the jaw (malocclusion), and may be affecting as many as 75 million Americans.[3]
History[edit]
Etymology[edit]
The English word joint is a past participle of the verb join, and can be read as joined.[17] Joint is derived from Latin iunctus,[17] past participle of the Latin verb iungere, join together, unite, connect, attach.[18]
The English term articulation is derived from Latin articulatio.[17]
Humans have also developed lighter, more fragile joint bones over time due to the decrease in physical activity compared to thousands of years ago.[19]
See also[edit]
Intra Articular Joint
References[edit]
Intra Articular Joint Programming
- ^ abcdWhiting, William Charles and RuggDynatomy, Stuart (2006) Dynamic Human Anatomy, Volume 10 p.40
- ^'Articulation definition'. eMedicine Dictionary. 30 October 2013. Retrieved 18 November 2013.
- ^ abcdefSaladin, Ken. Anatomy & Physiology. 7th ed. McGraw-Hill Connect. Web. p.274
- ^Standring, ed.-in-chief Susan (2006). Gray's anatomy : the anatomical basis of clinical practice (39th ed.). Edinburgh: Elsevier Churchill Livingstone. p. 38. ISBN0-443-07168-3.CS1 maint: Extra text: authors list (link)
- ^'Introduction to Joints (3) – Joints – Classification by Tissue Joining Bones'. anatomy.med.umich.edu. Archived from the original on 2011-06-08. Retrieved 2008-01-29.
- ^ abPrinciples of Anatomy & Physiology, 12th Edition, Tortora & Derrickson, Pub: Wiley & Sons
- ^'Articular Facet'. Medilexicon – Medical Dictionary. Retrieved December 19, 2013.
- ^'Foundational Model of Anatomy'. Archived from the original on December 19, 2013. Retrieved December 19, 2013.
- ^ ab'Introduction to Joints (2) – Joints – Classification by Movement'. anatomy.med.umich.edu. Archived from the original on 2011-07-18. Retrieved 2012-10-06.
- ^Samuel George Morton (1849) An Illustrated System of Human Anatomyp.119
- ^Henry Gray (1859) Anatomy, descriptive and surgicalp.136
- ^Henry Gray (1887) Anatomy, descriptive and surgicalp.220
- ^ abcPlatzer, Werner (2008) Color Atlas of Human Anatomy, Volume 1, p.28
- ^Armen S Kelikian, Shahan Sarrafian Sarrafian's Anatomy of the Foot and Ankle: Descriptive, Topographic, Functional p. 94
- ^'Introductory Anatomy: Joints'. Retrieved 2008-01-29.
- ^'Clinical Neuroanatomy and Neuroscience - 6th Edition'. www.elsevier.com. Retrieved 2019-03-17.
- ^ abcKlein, E. (1971). A comprehensive etymological dictionary of the English language. Dealing with the origin of words and their sense development thus illustration the history of civilization and culture. Amsterdam: Elsevier Science B.V.
- ^Lewis, C.T. & Short, C. (1879). A Latin dictionary founded on Andrews' edition of Freund's Latin dictionary. Oxford: Clarendon Press.
- ^Thompson, Helen. 'Switching to Farming Made Human Joint Bones Lighter'. Smithsonian Magazine. Smithsonian, 22 December 2014. Retrieved 28 November 2016.
External links[edit]
Wikimedia Commons has media related to joints. |
Intra Articular Joint Program Exercises
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