Intrinsic joint tissue repair by joint distraction

Introduction Joint distraction is a surgical technique that has been used to treat a variety of joint diseases, including degenerative arthropathies such as osteoarthritis and chondrolysis. In this critical review, we described the effect of joint distraction treatment. Materials and methods The systematic search was specifically aimed at preclinical and clinical publications about joint distraction in subjects with degenerative cartilage damage. After literature screening, 30 publications were included, reporting on the treatment of degenerative arthropathies of hip, ankle and knee. Results Joint distraction has been found to reduce pain and improve joint function in both preclinical and clinical studies. Furthermore, structural tissue repair is shown. Although well documented, the clinical studies are of limited quality. Only two randomized controlled trials, both on ankle joint distraction and both with limited number of patients, were included. Furthermore, most studies have modest follow-up periods of 1 and 2 years. Conclusion The results on structural repair induced by this treatment may lead to a better understanding. of the regeneration capacity of joint tissues in degenerative joint diseases. Introduction Osteoarthritis (OA) is a degenerative joint disease mainly characterized by cartilage loss. This leads to a decreased joint space width (JSW), frequently accompanied by mild synovial tissue inflammation and subchondral bone changes, such as sclerosis, subchondral cysts and osteophyte formation1. In a more advanced state of the disease, most patients experience pain and loss of function. Common surgical treatment in this end stage of disease is an arthrodesis or joint replacement. For younger physically active patients (<65 years), joint replacement is not the ultimate solution due to a limited lifespan. As such, there is a need for strategies that preserve the joint and treatments aiming at cartilage tissue repair. One of the joint-preserving treatments available is joint distraction, enabling intrinsic joint tissue repair supposedly due to regaining proper biochemical and biomechanical joint homeostasis. Joint distraction is a surgical technique in which two joint surfaces are fully separated to a certain extent by an external fixator frame for a limited period of time. During this separation, further wear and tear of the affected joint is preserved by full mechanical unloading2. The general opinion is that the osteoarthritic joint cannot repair itself; however, repair of joint tissues in addition to clinical benefit has been claimed by joint distraction in several preclinical and clinical studies. These studies demonstrate that under specific circumstances intrinsic cartilage repair is actually possible. In this crtitical review, we describe data from preand clinical studies on joint distraction, focussing on the larger joints, in relation to tissue repair and clinical benefit. Materials and methods For joint distraction, also called arthrodiatasis that consists of the Greek words arthro (joint), dia (through) and tasis (to stretch out), a systematic approach was used. PubMed, EMBASE and Cochrane libraries were searched for the words ‘distraction OR arthrodia(s)tasis AND joint OR articul*’ (December 2012). Titles and abstracts were screened for inclusion and exclusion criteria as formulated in the flow chart ( Figure 1). Full text screening designated publications focussing on restoration of degenerative joint damage with temporarily used external fixation devices in animal in vivo and clinical studies. Excluded were analyses without original data, studies in patients with intra-articular fractures or soft-tissue joint contractures, treatments with intraoperative use of distraction without the purpose of tissue regeneration, and treatments with permanent implantation of distraction devices. Screening the reference lists of relevant publications identified additional papers. Results Joint repair by joint distraction treatment in preclinical animal models After screening, seven preclinical animal studies were identified ( Table 1). Six of them had the knee as joint target and one study described joint distraction in a spine model3. It must be considered that the animal models described use traumainduced cartilage (and bone) damage * Corresponding author Email: S.Mastbergen@umcutrecht.nl †Authors contributed equally. 1 Rheumatology and Clinical Immunology, University Medical Center Utrecht, the Netherlands 2 Limb Reconstruction Center, Department of Orthopedics, Maartenskliniek Woerden, the Netherlands 3 Limb Reconstruction Center, Department of Orthopedics, University Medical Center Utrecht, the Netherlands


Introduction
Osteoarthritis (OA) is a degenerative joint disease mainly characterized by cartilage loss.This leads to a decreased joint space width (JSW), frequently accompanied by mild synovial tissue inflammation and subchondral bone changes, such as sclerosis, subchondral cysts and osteophyte formation 1 .In a more advanced state of the disease, most patients experience pain and loss of function.Common surgical treatment in this end stage of disease is an arthrodesis or joint replacement.For younger physically active patients (<65 years), joint replacement is not the ultimate solution due to a limited lifespan.As such, there is a need for strategies that preserve the joint and treatments aiming at cartilage tissue repair.
One of the joint-preserving treatments available is joint distraction, enabling intrinsic joint tissue repair supposedly due to regaining proper biochemical and biomechanical joint homeostasis.Joint distraction is a surgical technique in which two joint surfaces are fully separated to a certain extent by an external fixator frame for a limited period of time.During this separation, further wear and tear of the affected joint is preserved by full mechanical unloading 2 .
The general opinion is that the osteoarthritic joint cannot repair itself; however, repair of joint tissues in addition to clinical benefit has been claimed by joint distraction in several preclinical and clinical studies.These studies demonstrate that under specific circumstances intrinsic cartilage repair is actually possible.
In this crtitical review, we describe data from pre-and clinical studies on joint distraction, focussing on the larger joints, in relation to tissue repair and clinical benefit.

Materials and methods
For joint distraction, also called arthrodiatasis that consists of the Greek words arthro (joint), dia (through) and tasis (to stretch out), a systematic approach was used.Pub-Med, EMBASE and Cochrane libraries were searched for the words 'distraction OR arthrodia(s)tasis AND joint OR articul*' (December 2012).Titles and abstracts were screened for inclusion and exclusion criteria as formulated in the flow chart ( Figure 1).Full text screening designated publications focussing on restoration of degenerative joint damage with temporarily used external fixation devices in animal in vivo and clinical studies.Excluded were analyses without original data, studies in patients with intra-articular fractures or soft-tissue joint contractures, treatments with intraoperative use of distraction without the purpose of tissue regeneration, and treatments with permanent implantation of distraction devices.Screening the reference lists of relevant publications identified additional papers.

Joint repair by joint distraction treatment in preclinical animal models
After screening, seven preclinical animal studies were identified ( Table 1).Six of them had the knee as joint target and one study described joint distraction in a spine model 3 .It must be considered that the animal models described use traumainduced cartilage (and bone) damage   Remodelling of the damaged joint surface of the knee joint after joint distraction treatment has been demonstrated in three animal studies [4][5][6] .In these rabbit models, joint distraction caused joint repair after resection of the entire articular (bone-cartilage) surface of the tibial plateau and in a large osteochondral defect model 7 .Two studies on knee joint distraction demonstrated adverse effects on cartilage integrity, probably influenced by the test models used.Karadam et al. 8 used a model of cartilage chondrocyte death that can be questioned as a representative model of joint degeneration 9 .van Valburg et al. 10 used the anterior cruciate ligament tear dog model that is characterized by permanent joint instability as a trigger for OA and as such not very suitable to allow follow-up.This might explain why in the latter study improvement in structural repair (proteoglycan content) could not be demonstrated, although beneficial changes were seen in chondrocyte activity as measured by proteoglycan synthesis and release.
Changes in cartilage integrity are considered to take time and could be missed without or with short followup.This is supported by recently presented interim data 11 on joint distraction applied in the canine Groove model of OA, a model with a single trigger for OA allowing longer follow-up.In comparison with a non-treated OA group, cartilage proteoglycan content and chondrocyte activity were found to show statistically significant improvement together with macroscopically and histologically OARSI cartilage damage score improvements.During follow-up, loading was examined by force plate analysis as surrogate measurement of joint pain and function.OA-related impaired stance and brake forces regained normal levels again after treatment, in comparison with the control group and baseline values.This study supports the idea that structural joint modification and clinical improvement are possible due to joint distraction.

Joint repair by joint distraction treatment in clinical studies
In humans, joint distraction is generally performed in weight-bearing joints, like the ankle, knee and hip, although reports of smaller (nonweight-bearing) joints have been published as well (Figure 2).Most of the time structural repair parameters, such as changes in JSW and bone density, are analysed indirectly with radiography (X-ray), magnetic resonance imaging (MRI) or computed tomography (CT).Clinical parameters as pain and function are measured by the use of questionnaires (e.g.WOMAC or Likert scale).

Hip joint distraction
The first report of joint distraction was treatment of the hip 12 (Table 2).In 80 patients (age 9-69) with several different causes of joint degeneration (e.g.OA, osteonecrosis and chondrolysis), a hinged frame was applied for 1.5-2.5 months.Pain levels decreased and both function and mobility improved, supported by an increase in JSW on X-ray.Only three adverse events were reported of patients experiencing pain around the pelvic pins.In four patients with inflammatory arthropathy, the results were uniformly disappointing.In 2005 13 and 2009 14 , two other studies on hip joint distraction were published with only adolescent patients, again showing improvement in pain and function accompanied by increased JSW.
It is remarkable that this quite successful treatment was not further applied in daily clinic.Causes may be Licensee OA Publishing London 2013.Creative Commons Attribution License (CC-BY) The Ilizarov apparatus is a thin wire circular frame fixed or with a hinge.ACLT = anterior cruciate ligament transection.GWB = gradual weight bearing.CPM = continuous passive motion.CT = computed tomography.
addition, the risk of adjacent joint degeneration is prevented.The studies included reported different study designs (case study, retrospective, prospective and randomized controlled trials) and structural parameters evaluated ( cartilage growth, subchondral bone density and decrease of bone cysts).
Cartilage growth, defined as a modest 15,17,23 to significant 16,18,20,26 increase of the JSW on weight-bearing X-rays, is analysed only in 7 out of 12 studies.Unfortunately, not all studies used standardized X-rays leading to potentially biased measurements due to possible differences in positioning during follow-up.Marijnissen et al. 18 dissolved the bias created by differences in follow-up examinations using standardized X-rays with an aluminium step wedge 27 .This wedge calibrates for JSW and bone density measurements.In two studies 22,26 , increase of cartilage tissue in the joint was evaluated with MRI.
Statistically significant and clinically relevant decrease in subchondral bone density, as measured on Xrays, has been demonstrated in three studies 18,20,26 .In addition to bone density, a decrease of bone cysts on MRI or CT is reported in three separate studies as well 22,24,26 .These bone changes are particularly interesting, as normalization of subchondral bone 2 years after ankle distraction correlates with a decrease of pain (R = 0.69, P = 0.002) 24 .
In all studies, structural tissue improvements were corroborated with significant clinical improvements in pain and mobility.In three studies, prolonged follow-up after treatment was reported.These studies showed sustained clinical improvement for periods of 5 years 20,21 and 10 years 19 .In the latter, a success rate of 73% was reported for at least 7 years.Adverse events during and following ankle joint distraction were pin-tract infections, reported in six studies, and neuropraxia in 11 patients, three of whom were with persisting complaints 19,25 .A 12 shows hip joint distraction with the use of a DeBastani frame.B 23 ,C 17 show ankle joint distraction with the use of an Ilizarov external fixation frame.D 31 shows knee joint distraction with bilateral monotubes external fixation.E,F 28 is a hinged custom made knee distraction device.G 36 shows PIP joint distraction of the finger (hinged Compass frame) and H 35 shows IP distraction of the thumb ( hinged Ilizarov frame).I 37 is joint distraction of the metatarsal joint of the foot with a custom made frame.D 31 shows knee joint distraction with bilateral monotubes (Stryker ® ) external fixation.E,F 28 is a hinged custom-made knee distraction device.G 36 shows PIP joint distraction of the finger (hinged compass frame) and H 35 shows IP distraction of the thumb (hinged Ilizarov frame).I 37 is joint distraction of the metatarsal joint of the foot with a custom-made frame.method and device related-distraction of the femoral head out of the acetabulum can be difficult due to osteophytes, distraction in a spheroidal joint during movement is challenging and pelvic bone pin loosening resulting in pin-tract infection is frequent.

Ankle joint distraction
After hip joint distraction, studies on ankle joint distraction were started.

Knee joint distraction
In case of severe knee OA, the most often indicated treatment at present is joint replacement surgery.Due to ageing and the on-going obesity pandemic, both being major predispositions for joint degeneration, there is an exponential increase in knee joint replacement and a high need for strategies that preserve the knee joint.Despite this, only four studies on joint distraction in patients with knee OA have been published to date and are summarized in Table 2C [28][29][30][31][32] .
In these studies, cartilage regeneration and bone density were measured by X-ray and MRI analysis.Specific analyses for bone cysts were not performed, and most studies were carried out retrospectively (three out of four).Nonetheless, significant increase of JSW on weight-bearing Xrays was demonstrated in all studies.
Only one study 31 used standardized X-rays as described above for ankle joint distraction, which allows for digital analysis 33 .Arthroscopic evaluation [28][29][30] and/or MRI evaluation 30,31 showed cartilage resurfacing and cartilage repair after joint distraction treatment.On MRI, a significant increase in cartilage thickness and volume was seen.In addition to the structural tissue changes, significant improvement in pain and mobility was reported in all studies.In the randomized controlled trial by Aly et al. 32 , significant improvement in pain and mobility was demonstrated for the group treated with arthroscopic debridement and knee joint distraction in comparison with arthroscopic debridement treatment alone.Besides pin-tract infections in three studies, other reports on adverse events included one patient with a deep-vein thrombosis 32 and three patients with a lung embolism 31,32 .
Discussion persists on the quality of the newly formed cartilage in the joint.Taking biopsies is argued ethically.Intema et al. 31 tried to avoid this by analysing biochemical markers for collagen type II turnover and showed an increase of synthesis over release, suggesting the hyaline nature of the newly formed tissue.Qualitative MRI examinations like dGEMRIC or T1rho 34 have potential added value in determining the quality of newly formed tissue; however, so far this has never been reported in joint distraction studies.

Other joints
Besides the larger joints, three clinical studies on treatment of smaller joints were found (Table 2D) [35][36][37]    joints.Despite the fact that the hand joints are non-weight-bearing joints, for both foot and hand joints, promising results were reported in case reports.Two studies report structural tissue repair, analysed with X-ray and MRI 35,37 , showing significant increase in JSW, increase in cartilage thickness on MRI and normalization of bone.In all studies, treatment resulted in improvement in pain and mobility.It was reported that one patient developed a septic arthritis after PIP joint distraction 36 .

Discussion
The authors have referenced some of their own studies in this review.These referenced studies have been conducted in accordance with the Declaration of Helsinki (1964), and the protocols of these studies have been approved by the relevant ethics committees related to the institution in which they were performed.All human subjects, in these referenced studies, gave informed consent to participate in these studies.Joint distraction in treatment of degenerative joint disorders has been applied for almost 20 years now, with mostly positive results demonstrating actual structural tissue repair, pain decrease and improvement of function remaining in the follow-up period (ranging from 0.75 till 10 years).However, only one study could demonstrate a correlation between structural tissue repair and clinical improvement 24 .The limited number of patients included per study can explain lack of such a relation.Due to the different study designs, a meta-analysis of all patients is not feasible.
Although the presented studies were well documented, they are still of limited quality as only three randomized controlled trials are described.These studies, two on ankle joint distraction and one on knee joint distraction, have a limited number of patients included.Furthermore, these studies have modest follow-up periods of 1, 2 and 5 years.The longest follow-up described until now is 10 years after ankle distraction in severe ankle OA patients 19 .That study was performed retrospectively and included only 22 patients.
The randomized controlled trial by Saltzman et al. 25 showed that a hinged ankle distraction frame is clinically more effective and has better structural results in addition to a higher patient convenience compared with a stiff frame.Structural tissue repair was demonstrated in favour of joint distraction treatment in combination with arthroscopic debridement compared with arthroscopic debridement alone, for both ankle and knee 18,32 .In all trials, heterogeneity of patients was present, and most patients had several surgical interventions before.Patients often had no other option, in regular care, than arthrodesis or joint replacement.Some concerns persist on possible latent bone infection due to pin-tract infection during joint distraction, increasing the risk of infection after prosthesis surgery.To date, however, no data are available, whereas in some studies uncomplicated prosthesis placement was reported after joint distraction treatment in case of function loss.
Joint distraction induces joint tissue repair and cartilage growth in like autologous chondrocyte implantation or disease-modifying osteoarthritic drug treatment.Only with the addition of such sensible and united evaluation of outcomes, joint distraction might be implemented in daily clinical orthopaedic practice.areas of denuded bone, suggesting that joint distraction might also be beneficial for treatment of local cartilage defects as seen in the preclinical models 4 .This hypothetically enlarges the indication of joint distraction in case of cartilage damage.Besides the application as a treatment, joint distraction now provides for the first time the opportunity to study the process of intrinsic cartilage repair.Apparently joint distraction results in a biochemical and biomechanical environment that facilitates (and might even be a prerequisite for) cartilage repair.
Results of future studies should position joint distraction also alongside more common joint-preserving treatments such as microfracture and high tibial osteotomy in a randomized controlled design.Additionally, results should be recorded for longer follow-up periods to investigate the endurance of clinical improvement and structural tissue repair.Furthermore, patient characteristics should be accurately surveyed to determine for which type of OA patient 38 joint distraction is the most optimal treatment.

Conclusion
Joint distraction is a promising jointpreserving treatment of degenerative disorders, resulting in clinical improvement and actual structural joint tissue repair.No other treatment so far enabled such clear intrinsic joint tissue changes.However, it is important that future studies focus on selection of patients, considering phenotypes of onset and stage of the degeneration process to optimize treatment results and provide a most optimal cost-effective treatment.Furthermore, effort is needed in biochemical and imaging markers to demonstrate more subtle changes in tissue repair, preventing the need for biopsies.It would be interesting to see how this approach can work synergistic in combination with other promising cartilage repair therapies,

Figure 1 :
Figure 1: Flow chart.developed in a relatively short time span.This contrasts to the slow onset of joint degeneration (OA) in the human situation.Remodelling of the damaged joint surface of the knee joint after joint distraction treatment has been demonstrated in three animal studies[4][5][6] .In these rabbit models, joint distraction caused joint repair after resection of the entire articular (bone-cartilage) surface of the tibial plateau and in a large osteochondral defect model7 .Two studies on knee joint distraction demonstrated adverse effects on cartilage integrity, probably influenced by the test models used.Karadam et al.8 used a model of cartilage chondrocyte death that can be questioned as a representative model of joint degeneration9 .van Valburg et al.10 used the anterior cruciate ligament tear dog model that is characterized by permanent joint instability

Figure 2 .
Figure 2. Different techniques of joint distraction in clinical studies.A12  shows hip joint distraction with the use of a DeBastani frame.B23 ,C17 show ankle joint distraction with the use of an Ilizarov external fixation frame.D31 shows knee joint distraction with bilateral monotubes external fixation.E,F 28 is a hinged custom made knee distraction device.G36 shows PIP joint distraction of the finger (hinged Compass frame) and H35 shows IP distraction of the thumb ( hinged Ilizarov frame).I 37 is joint distraction of the metatarsal joint of the foot with a custom made frame.

Figure 2 :
Figure 2: Different techniques of joint distraction in clinical studies.A 12 shows hip joint distraction with the use of a DeBastani frame.B 23 , C 17 show ankle joint distraction with the use of an Ilizarov external fixation frame.D31 shows knee joint distraction with bilateral monotubes (Stryker ® ) external fixation.E,F 28 is a hinged custom-made knee distraction device.G36 shows PIP joint distraction of the finger (hinged compass frame) and H35 shows IP distraction of the thumb (hinged Ilizarov frame).I 37 is joint distraction of the metatarsal joint of the foot with a custom-made frame.

Table 1 Animal models Joint author, year Species (age in months); treated; un- treated controls Joint damage model; treatment; duration (weeks); follow-Up (weeks) Structural outcomes
For citation purposes: Wiegant K,vanHeerwaarden RJ, van Roermund PM, Mastbergen SC.Intrinsic joint tissue repair by joint distraction.OA Arthritis 2013 Feb 02;1(1):4.Competing interests: none declared.Conflict of interests: none declared.All authors contributed to conception and design, manuscript preparation, read and approved the final manuscript.All authors abide by the Association for Medical Ethics (AME) ethical rules of disclosure.

Table 2A Clinical studies, hip Author, year Patient character- istics (number, age (years), disease) Case report Retrospective Prospective Random contr Treatment; duration (months); follow-up (years) Clinical and structural outcomes
. Degenerated ankle joints, more common at an early age (30-40 years of age), are frequently fused with an arthrodesis, being a safe and cost-effective treatment.The application of ankle joint distraction is aimed at joint preservation due to intrinsic joint tissue repair in combination with clinical improvement.In Licensee OA Publishing London 2013.Creative Commons Attribution License (CC-BY) For citation purposes: Wiegant K,vanHeerwaarden RJ, van Roermund PM, Mastbergen SC.Intrinsic joint tissue repair by joint distraction.OA Arthritis 2013 Feb 02;1(1):4.Competing interests: none declared.Conflict of interests: none declared.All authors contributed to conception and design, manuscript preparation, read and approved the final manuscript.All authors abide by the Association for Medical Ethics (AME) ethical rules of disclosure.MRI = magnetic resonance imaging.JSW = joint space width.
. Joint distraction was applied in foot and hand

Table 2C Clinical studies, knee
Ilizarov apparatus is a thin wire circular frame fixed or with a hinge.MRI = magnetic resonance imaging.JSW = joint space width. The

Table 2B (continued)
Ilizarov apparatus is a thin wire circular frame fixed or with a hinge.MRI = magnetic resonance imaging.CT = computed tomography.JSW = joint space width.BD = bone density.BC = bone cysts. The