Skip to main content
Download PDF

The effect of autologous adipose derived mesenchymal stem cell therapy in the treatment of a large osteochondral defect of the knee following unsuccessful surgical intervention of osteochondritis dissecans – a case study

BMC Musculoskeletal Disorders volume 18, Article number: 298 (2017) Cite this article

Abstract

Background

A prospective analysis of the effect of autologous adipose derived mesenchymal stem cell (MSC) therapy in the treatment of an osteochondral defect of the knee with early progressive osteoarthritis following unsuccessful surgical intervention of osteochondritis dissecans (OCD).

Case presentation

After failed conventional management of OCD a patient undergoes intra-articular MSC therapy. Patient outcome measures included the Numeric Pain Rating Scale (NPRS), the Western Ontario and McMaster Universities Arthritis Index (WOMAC) and the Knee Injury and Osteoarthritis Outcome Score (KOOS). Structural outcome was assessed using MRI with the novel technique of T2 mapping used to indicate cartilage quality. Following MSC therapy the patient reported improvement in pain and function as measured by NPRS, WOMAC and KOOS. Repeat MRI analysis showed regeneration of cartilage. MRI T2 mapping indicated hyaline like cartilage regrowth.

Conclusion

In this report, the use of MSCs, after unsuccessful conventional OCD management, resulted in structural, functional and pain improvement. These results highlight the need to further study the regenerative potential of MSC therapy.

Trial registration

Australian and New Zealand Clinical Trial Registry Number - ACTRN12615000258550 (Date registered 19/03/2015 – retrospectively registered).

Peer Review reports

Background

Osteochondritis dissecans (OCD) was a term first used to describe the development of loose bodies within a joint with no prior evidence of significant trauma [1]. Whilst the pathophysiology of OCD remains uncertain, it is accepted that it is a subchondral lesion characterized by variable degrees of bone resorption, collapse, sequestration and overlying articular cartilage disruption [2, 3].

Commonly held belief is that OCD may result from inflammation, vascular deficiency, genetic predisposition or repetitive microtrauma. Interestingly, OCD was initially termed osteochondritis due to a belief that it resulted from an inflammatory process [4]. Histological studies have, however, demonstrated areas of necrosis within OCD lesions rather than an inflammatory process. Repetitive microtrauma has become an accepted preceding stimulus due to the observed increased incidence of OCD amongst the athletic population [5–7].

OCD typically presents as activity related knee pain without prior history of trauma [8, 9]. Whilst it may affect several joints it is commonly described in the knee where it is most commonly seen in the lateral aspect of the medial femoral condyle (51%). Other areas of the knee include the central medial femoral condyle (19%), lateral femoral condyle (17%), medial edge of the medial femoral condyle (7%) and the patella (7%), with up to 20% of lesions being bilateral [7, 10, 11].

OCD lesions are often described as stable or unstable with stable lesions considered to be suitable for non-operative conservative management [7, 12]. De Smet and colleagues, using a T2 weighted MRI technique, noted four criteria with an observed correlation with instability – 1) a high signal line beneath the lesion, 2) a focal area of overlying articular cartilage defect, 3) a fracture of the articular cartilage, 4) subchondral cyst formation [13, 14]. Using these criteria Kijowski and colleagues showed that if all four criteria are present this correlated with a high surgical observation of instability in adult OCD, though surprisingly this had low sensitivity in predicting instability in childhood OCD [15].

It is generally accepted that first line treatment for radiologically stable OCD lesions in children should consist of a non-operative management strategy [16, 17]. Protocols for non-operative management are however inconsistent and may include non-weight bearing, casting, protected weight bearing, bracing and / or activity modification. Rates of radiological healing with non-operative management have been reported to vary from 50 to 94% [18].

Surgical management of stable lesions that fail conservative management can include drilling, bone grafting and fixation [18–20]. Whilst arthroscopic drilling has become a commonly accepted practice and has a healing response of 82–98%, extra-articular trans-epiphyseal drilling has been proposed as an alternative as it does not violate the overlying intact articular cartilage [21–23].

Surgical fixation of unstable lesions may include curettage and drilling of the underlying bone, bone grafting if necessary and fixation of the OCD using compression screws or bio-absorbable implant/nails [24]. In the case where the OCD lesion is fragmented and unable to undergo surgical fixation then the lesion/fragment should be removed. Whilst removal of the loose body may result in short term pain improvement, up to 79% of patients will have degenerative findings on plain film at 11 years follow-up [25]. This is in keeping with observed progression of osteochondral defects to osteoarthritis [26, 27]. The observed progressive joint degeneration has seen the exploration of additional interventions to promote healing.

Whilst microfracture remains a technique commonly used for osteochondral defects, its use in OCD is less well defined and outcome may arguably be influenced by the pathology of the subchondral bone that is observed in OCD. A randomised study comparing microfracture to osteochondral autologous transplantation in OCD demonstrated similar short-term results. The microfracture group, however, deteriorated with time and exhibited a failure rate of 41% at 4 years post operatively. Research by Britterg and colleagues, using autologous chondrocyte implantation, has shown excellent outcome in the management of chondral defects with success seen in osteochondral lesions as deep as 9 mm [28].

The observed progression of osteochondral defects to early degenerative osteoarthritis poses a particular problem with patients with OCD who fail surgical fixation or alternative treatment of the defect following removal of an unstable fragment. The role of mesenchymal stem cells (MSCs), with their inherent ability to differentiate along different cell lines of mesodermal lineages (including osteoblasts and chondrocytes) coupled with their observed paracrine expression of several growth factors and cytokines which promote tissue repair, has seen a renewed focus on their potential in orthopaedic regenerative techniques [29–32]. Within both pre-clinical and clinical literature there is a growing indication of the possible efficacy of MSC therapy in the management of osteochondral defects and similarly in osteoarthritis.

Preclinical trials using techniques similar to autologous chondrocyte transplantation but replacing chondrocytes with MSCs have shown positive outcomes with noted formation of hyaline like cartilage at the site of repair [33, 34]. Wakitani and colleagues have used this similar technique in a limited clinical trial to successfully treat isolated cartilage defects [35].

The use of microdrilling (a technique similar to microfracture) in combination with intra-articular MSC injections in the treatment of osteochondral defects has shown initial promise with later biopsy showing histopathology consistent with type II collagen and hyaline like cartilage formation [36]. The authors of this case report are also involved in a concurrent randomised controlled trial assessing a similar microfracture technique in combination with autologous adipose derived stem cells [37].

Whether stem cell therapies have similar observable benefits in the treatment of osteochondritis dissecans is yet to be formally studied.

Case presentation

Medical history and assessment

A 26 year old male presented with increasing right knee pain and functional debility with a history of osteochondritis dissecans and having had multiple past surgical interventions. He was otherwise well, though was currently unable to perform any activities that involved prolonged weight bearing and found it increasingly difficult to continue his occupation within allied health care.

The patient noted an initial diagnosis of OCD at age 13. This was appropriately treated conservatively with a period of reduced load and protected weight bearing. He was later able to return to sport - which included Australian Rules football.

Due to recurrence of pain he underwent arthroscopic examination at age 14. Arthroscopic probing of the OCD lesion indicated that it was stable and conservative management and further unloading was pursued. The patient failed conservative management and 1 year later underwent a repeat arthroscopy at which time an unstable 3 cm × 3 cm lesion involving his medial femoral condyle was removed. It was felt that as the fragment had little subchondral bone that direct repair was not achievable. A further arthroscopy was performed 8 months later and a chondral biopsy was taken for later autologous chondrocyte transplantation. At the time it was noted that no healing had occurred at the site of the defect.

Two months later, the treating surgeon, using a lateral arthrotomy approach, patched the defect using a matrix induced autologous chondrocyte implant (MACI). The patch was fixed in place using fibrin glue. One year later, and due to persistent discomfort and swelling of the knee, the patient underwent a further arthroscopy. It was noted that the outer rim of the MACI patch had incorporated well, yet an inner area of 1.5 cm × 1.5 cm had failed to fill completely.

At age 23 and due to troubling discomfort and mechanical features of instability the patient underwent another arthroscopy. Numerous loose bodies within both the medial and lateral compartments were washed out. The area of the past OCD and MACI graft had failed with exposure of underlying subchondral bone and formation of a large subchondral cyst. Unstable edges of the area of MACI graft were debrided but as the entrance to the subchondral cyst was small a surgical decision was made not to further expose nor debride the cavity.

Failing to symptomatically improve, the patient underwent a further arthrotomy with debridement of the subchondral cyst, after which it was filled with bone graft substitute cortico-cancellous crunch granules. A periosteal flap taken from the medial border of the tibia was then applied over the lesion. The patient underwent a final arthroscopy at age 25 for debridement of an unstable fibro-cartilaginous cap at the site of the past periosteal flap.

In total the patient underwent seven separate operations.

Initial examination upon presentation showed evidence of a moderate right knee effusion. The patient had full range of motion and the knee was stable.

Radiological examination included both X-Ray and MRI. X-Ray confirmed early degenerative change with intercondylar notch osteophytes consistent with Kellgren-Lawrence Grade II. There was noted concavity to the lateral aspect of the medial femoral condyle consistent with the previous area of OCD (Fig. 1). MRI showed marked abnormality over the weight bearing portion of the medial femoral condyle measuring 2.3 cm × 1.5 cm. The subchondral cyst had successfully been debrided and grafted and was no longer present on MRI. A thin layer of hyper-intense tissue incompletely covered the area of abnormal cortex (at site of past bone substitute grafting) (Fig. 2). The area of pathology had a modified International Cartilage Repair Society (ICRS) score of 4. In addition to routine MRI protocols, the method of T2-relaxation time cartilage mapping was used. T2 mapping indicated significantly elevated values within the thin layer overlying the osteochondral defect but also elevated values within the surrounding cartilage (Fig. 3).

Fig. 1
figure 1

X-ray of the knee showing flattening of the medial femoral condyle and intercondylar notch osteophyte formation – Kellgren Lawrence Grade II

Full size image
Fig. 2
figure 2

Pre-Treatment Proton Density (PD) weighted Coronal and Sagittal MRI images of the knee showing the isolated chondral defect involving the central weight bearing area of the medial femoral condyle

Full size image
Fig. 3
figure 3

Pre-Treatment MRI T2 mapping of the medial compartment of the knee indicating elevated hydration of the cartilage in the area surrounding the OCD and also of the thin layer of tissue which partially covered the defect

Full size image

The patient sought advice regarding further interventions that may improve both his current symptoms but also his long-term prognosis as he wished to avoid progressive degeneration and early joint arthroplasty. After careful consideration and as he now had features of early degenerative change he was assessed as suitable for inclusion in an ethics approved, registered case series on the use of adipose derived MSC therapy in the treatment of osteoarthritis.

The patient was given written information regarding the use of MSC therapy, including relative risks of MSC therapy and also relevant treatment alternatives that could otherwise be explored. Formal written informed consent was obtained prior to commencing therapy.

Source of mesenchymal stem cells

Adipose tissue was chosen as a source of MSCs due to ease of harvest, abundance of MSCs and the observed chondrogenic potential of adipose derived MSCs. Bone marrow aspirate was considered an alternative source or MSCs but surprisingly has a relative paucity of MSCs – comprising .001–.02% of the mono-nucleated cell population in comparison to ~1–7% found within adipose tissue [38–40]. Many studies have indicated similar chondrogenic potential between bone marrow derived and adipose derived MSCs [41].

Autologous adipose derived mesenchymal stem cell preparation

The patient underwent an abdominal liposuction harvest procedure. Using a lateral abdominal approach, the subcutaneous fat was infiltrated with an anaesthetic tumescent fluid preparation comprising of 30 mls of 2% lignocaine, 1 ml of 1:1000 adrenaline, 1 ml of 8.4% bicarbonate suspended in a normal saline solution (total 1000 ml). Using a 4 mm lipo-aspirate cannula, 60 mls of adipose tissue and tumescent fluid was successfully harvested and collected within a sterile medical grade single use Shippert Tissu-Trans Collection filter (Shippert Medical, Colorado, USA). The sample was then transferred directly from the theatre via an air lock system to a laboratory clean room facility operated by Magellan Stem Cells (Magellan Stem Cells, Melbourne, Australia).

Autologous MSCs were isolated and expanded from the harvested adipose tissue using previously published protocols [42]. The processing of the lipo-aspirate was performed within the environment of a Biological Safety Cabinet (BSC) Class II using strict sterile techniques.

Stromal Vascular Fraction (SVF) obtained from the lipo-aspirate was culture purified using standard growth media containing Minimum Essential Media Eagle (MEM) supplemented with 2 mM glutamate and 10% Fetal Bovine Serum (FBS) (HyClone – GE Healthcare, USA). The cells were cultured under hypoxic conditions with 5% CO2 at 37 °C. Non-adherent cells were removed by washing with sterile phosphate buffered saline (PBS). The adherent cells were cultured until 80% confluency in freshly added growth media. The cultured purified cells were then harvested at passage 0 (P0). These cells were further plated to tissue culture flasks and expanded up to passage 2 (P2). The cells were harvested and analyzed for cell count and viability using a Muse Cell Analyzer (Merck Millipore, USA). The harvested cells were washed three times to remove FBS and cryopreserved in cryovials using clinical grade qualified MSC cryoprotectant media and following a previously validated control rate freezing technique of 1 °C/min [43, 44]. The cryovials were transferred to liquid nitrogen storage until use.

At completion of isolation and expansion, the cells underwent independent phenotypic analysis at Monash University and were characterised by flow cytometry using Florescent Activated Cell Sorting (FACS). Using standards established by the Internal Society of Cellular Therapy, the cells were assessed for the presence of positive surface markers CD 90, CD 73 and CD 105 and absence of hematopoetic surface markers CD14, CD19, CD34 and CD45 [45] (Tables 1-2 and Fig. 4). A further sample was sent for independent sterility testing for microbial growth.

Table 1 Flow Cytometry Dot-Plot surface marker analysis showing results consistent with mesenchymal stem cells as per the International Society of Cellular Therapy guidelines
Full size table
Table 2 Flow Cytometry Histogram surface marker analysis showing results consistent with mesenchymal stem cells as per the International Society of Cellular Therapy guidelines
Full size table
Fig. 4
figure 4

Flow Cytometry Dot-Plot and Histogram surface marker analysis. The pink and purple histograms represent isotope control and the tested cell sample respectively

Full size image

Injection method

Prior to the intra-articular injection the cryopreserved cells were retrieved from the liquid nitrogen Dewar and thawed quickly within a sterile 37 °C water bath. The thawed cells were then washed in chilled PBS to remove cryoprotectant media, centrifuged and the resultant cell pellet re-suspended in clinical grade 0.9% normal saline. The cells were again analyzed for cell count and viability post thaw using the Muse Cell Analyzer. The cells were injected within 30 min of thawing.

The patient received a total of 118 million MSCs (viability 98%) suspended in 3mls of normal saline at commencement of therapy. A second injection of 50 million MSCs (viability 95%) at 6 months was also given.

At both injection time points the patient’s right knee was prepped using a chlorhexidine solution and draped. 2 mls of 1% lignocaine was infiltrated subcutaneously at the site of injection. Using a supero-lateral approach to the patella, and under sterile conditions and ultrasound guidance, the MSCs suspended in 3 mls of normal saline were injected into the intra-articular space.

Post injection rehabilitation

After the initial injection the patient was fitted with a medial compartment customised unloading knee brace to allow protected but full weight-bearing. This was achieved using an Ossur OA Unloader One brace (Ossur, Reykjavic, Iceland).

The patient was given post injection instructions, which included range of motion exercises and lower limb muscle activation exercises, and encouraged to perform repetitive low impact and low load exercises against minimal resistance on a stationary bike (continuous active motion versus continuous passive motion). This protocol was developed due to previously published evidence which has indicated the benefit of controlled load on cartilage health [46].

Potential side effects / risks

Importantly, recent systematic review and meta-analysis of previous clinical papers investigating the use of mesenchymal stem cell therapy – both intravascular and intra-articular applications – and including autologous, allogeneic and expanded MSC preparations has indicated that MSC therapy is safe. No adverse events including infection, death or malignancy have been recorded.

Saw and colleagues have documented a self-limited flare up with discomfort and swelling following intra-articular MSC therapy [36]. This was not considered a serious adverse event.

Relative risks of the liposuction harvest procedure include infection, bruising and post operative discomfort. Whilst the risk of infection is low, the patient received a single dose of prophylactic antibiotics prior to the procedure as part of accepted routine clinical practice [47].

Analysis methods and outcome measures

Prospective analysis of patient outcome to intra-articular MSC therapy included the following measures:

  1. 1.

    The Knee Injury and Osteoarthritis Outcome Score (KOOS). This is a validated scoring system intended for the assessment of knee injury that may result in post-traumatic knee osteoarthritis. The score consists of 5 subscales - pain, other symptoms, function in daily living, function in sport and recreation and knee related quality of life. Standardised answers to questions are given (5 Likert scale) and each question is assigned a score of 0–4. A normalized score is calculated for each subscale (100 indicates no symptoms and 0 indicates maximum symptoms) [48].

  2. 2.

    The Western Ontario and McMaster Universities Arthritis Index (WOMAC Index 3.0). This score is a validated quality of life score and quantitatively assesses the pain, stiffness and physical function in patients with symptomatic osteoarthritis [49].

  3. 3.

    The Numeric Pain Rating Scale (NPRS). The patient rates their knee pain intensity over the previous week on a scale of 0–10. The NPRS has been validated for use in people with knee osteoarthritis [50].

Outcome scores were completed at baseline, 1, 3, 6, 12 and 18 months post commencement of MSC therapy and recorded using the software program Clinical Intelligence (Clinical Intelligence, Melbourne, Australia).

Structural outcome was assessed using MRI imaging performed prior to commencement of therapy and again at 6 and 18 months post-treatment. Semi quantitative measures of the cartilage defect were obtained using a modified ICRS score [51]:

  • Grade 0: normal cartilage

  • Grade 1: focal blistering and intra-cartilaginous low-signal intensity area with an intact surface and bottom

  • Grade 2: irregularities on the surface or bottom and loss of thickness of less than 50%

  • Grade 3: deep ulceration with loss of thickness of more than 50%

  • Grade 4: full-thickness cartilage wear with exposure of subchondral bone.

In addition to routine MRI protocols, the method of T2-relaxation time cartilage mapping was used. T2 mapping assesses the water content of cartilage by giving a quantifiable value to the ability of free water protons to exchange energy and move through a cartilage matrix [52]. Observed increased water content resulting in an increased T2 relaxation time is an indication of chondral pathology. T2 mapping has been well studied and is an accepted and validated non invasive measure of cartilage quality [53].

Effect of MSC therapy on pain, function and structure

The numeric pain rating score increased at 1 month from 4 to 5 reflecting an initial self-limiting flare up (see Adverse Events). Follow-up at 6 months however showed a 50% improvement in NPRS from baseline and this had further improved by 75% with a pain score of 1 at completion of follow-up at 18 months (Fig. 5).

Fig. 5
figure 5

Numeric Pain Rating Score. Pain initially increased due to a self-limiting flare up following injection of MSC therapy. Thereafter it reduced and remained improved until completion of follow up at 18 months

Full size image

Knee Injury and Osteoarthritis Outcome Scores consistently improved across the period of follow-up (Fig. 6). At 6 months the patient’s Symptoms Score had improved by 44% and similarly his Sport and Recreational Score had improved by over 100%. These values showed continued improvement at 18 months. The measure of Quality of Life had improved at 18 months by greater than 400% above baseline.

Fig. 6
figure 6

Knee Injury and Osteoarthritis Outcome Score. All subscales of KOOS showed consistent improvement over the period of follow-up

Full size image

Reflecting the observed improvement in KOOS, the WOMAC Knee Score showed similar consistent improvement from baseline till completion of data collection. At 18 months, the Global WOMAC Score had improved by over 20% (Fig. 7).

Fig. 7
figure 7

Western Ontario and McMaster Universities Arthritis Index. Pain, stiffness and function improved following mesenchymal stem cell therapy

Full size image

Structural follow-up using MRI at both 6 months and 18 months showed significant increase in tissue covering the extensive OCD of the medial femoral condyle. Observed development of a subchondral plate suggested a layering effect from subchondral bone through to the chondral surface. There was smooth integration with the surrounding native cartilage at the periphery of the OCD (Figs. 8 and 9). Using the modified ICRS scoring system as described above, ICRS grade improved from 4 to 1.

Fig. 8
figure 8

Post-Treatment PD weighted Coronal and Sagittal MRI imaging at 6 months indicating articular cartilage regeneration at the site of the osteochondral defect with smooth integration with the surrounding joint surface

Full size image
Fig. 9
figure 9

Post-Treatment PD weighted Coronal andSagittal MRI imaging at 18 months indicating persistent articular cartilage regeneration at the site of the osteochondral defect

Full size image

T2 mapping at 6 months returned elevated values at the site of regenerative cartilage, consistent with high water content and immature cartilage (Fig. 10a). Further analysis at 18 months, however, indicated improved T2 values suggestive of progressive maturation of the regenerative tissue (Fig. 10b).

Fig. 10
figure 10

Post-Treatment MRI T2 mapping of the medial compartment of the knee. a 6 month T2 Mapping: Elevated values within the regenerated cartilage indicate immature cartilage or fibrocartilage morphology. b 18 month T2 Mapping: Improved values within both the deep and superficial layers indicate hyaline cartilage. This finding indicates cartilage maturation since previous imaging at 6 months

Full size image

Adverse events

Following initial MSC therapy the patient reported swelling and increased discomfort of the treated knee. The knee effusion persisted for 6 weeks. This was managed conservatively with application of ice, a compression bandage and simple analgesia. Due to this observed reaction the second injection at 6 months was reduced to 50 million MSCs (viability of 95%). The patient reported minor swelling and discomfort for 2 weeks, with no additional management required.

Discussion

This case study highlights the promise and emerging evidence of mesenchymal stem cell therapy in the treatment of articular pathology including isolated chondral lesions and osteoarthritis. Whilst part of a broader ethics approved and registered case series, this isolated case represents a unique observation due to the underlying pathology of Osteochondritis Dissecans and a history of subsequent failed surgical interventions.

Formal quantitative questionnaire based follow-up indicated consistent improvement in pain and function up to completion of data collection at 18 months. Perhaps the most striking observation was an improvement in Quality of Life (KOOS) by a factor of greater than 400% above pre-treatment baseline. This alone highlights the importance of emerging regenerative techniques.

Other treatment options including biological therapies such as platelet-rich plasma have also noted similar pain and function improvement in patients with symptomatic degenerative knee conditions [54–57]. The disease modification and structural improvement in the underlying articular pathology observed in this case study, however, suggests that MSC therapy may offer significant advantages in regards to changing the end point of joint degeneration – i.e. total joint arthroplasty.

Routine MRI follow-up showed evidence of appreciable improvement in cartilage volume and osteochondral architecture at the site of injury. Early MRI T2 mapping at 6 months indicated that the area of cartilage regeneration exhibited high water content suggestive of immature cartilage or fibrocartilage morphology. Later T2 mapping at 18 months indicated progressive maturation of cartilage from deep to superficial layers with more hyaline like cartilage morphology. Whilst a surgical biopsy would provide true histopathology of the regenerated tissue, a repeat arthroscopy, for purpose of biopsy only, was not felt to be justifiable.

Biological cartilage repair techniques are an emerging area of development with methods such as autologous chondrocyte implantation showing encouraging results [58]. Such techniques however may be limited by donor site morbidity, development of fibrocartilage due to down regulation of chondrocytes during ex vivo expansion and observed poor integration with neighbouring cartilage [59–61]. They are also limited to isolated chondral pathology, and are not transferrable to the more diffuse compartmental changes of osteoarthritis.

In this single case study, the use of isolated expanded adipose derived MSCs, resulted in the regeneration of articular surfaces and subsequent improvement in the patient’s pain and function where previous accepted therapies including autologous chondrocyte implantation had failed. The use of a simple injectable technique with no requirement for invasive intra-articular surgery with its associated risks and complications is an exciting possibility, particularly in the pathology of OA where there exists diffuse rather than isolated cartilage loss.

Whilst the capacity of MSCs to differentiate into chondrocytes has indicated their promise in the management of degenerative chondral pathologies, previous studies have not consistently shown their integration within articular cartilage [62, 63]. This suggests that the benefit of MSC therapy may in fact be achieved through cell to cell contact and paracrine mechanisms (i.e. cytokine expression) leading to a manipulation and improvement of the underlying disease process [32].

Importantly, there remains a number of variables unique to this case study that may be relevant to the observed improvement. The patient was young, had previous surgery which disrupted the osteochondral environment and had a history of OCD which itself may effect outcome and cellular response due to underlying osteochondral pathology. Whether such results would be achieved using a similar intervention in older patients, and with no prior history of OCD, is a question which remains to be answered.

Conclusion

Osteochondritis Dissecans is an important cause of non-traumatic joint pain in adolescents. Current accepted surgical techniques for isolated osteochondral lesions are limited by factors including technical difficulty, poor tissue integration and development of fibrocartilage. In this case study, mesenchymal stem cell therapy has shown promise in the treatment of osteochondral defects with evidence of structural, functional and pain improvement.

Further research is required to determine if the benefits of mesenchymal stem cell therapy are reproducible across a larger population and for other degenerative joint conditions including osteoarthritis.

Abbreviations

BSC:

Biosafety cabinet

FACS:

Florescent Activated Cell Sorting

FBS:

Fetal Bovine Serum

ICRS:

International Cartilage Repair Society

KOOS:

Knee Injury and Osteoarthritis Outcome Score

MRI:

Magnetic Resonance Imaging

MSC:

Mesenchymal stem cells

NPRS:

Numeric pain rating scale)

OCD:

Osteochondritis dissecans

PBS:

Phosphate buffered saline

WOMAC:

Western Ontario and McMaster Universities Arthritis Index

References

  1. Freiberg AH, Woolley PG. Osteochondritis dissecans: concerning its nature and relation to formation of joint mice. Am J Orthop Surg. 1910;28(3):477–94.

    Google Scholar 

  2. Crawford DC, Safran MR. Osteochondritis dissecans of the knee. J Am Acad Orthop Surg. 2006;14(2):90–100.

    Article  PubMed  Google Scholar 

  3. Kocher MS, Tucker R, Ganley TJ, Flynn JM. Management of osteochondritis dissecans of the knee: current concepts review. Am J Sports Med. 2006;34(7):1181–91.

    Article  PubMed  Google Scholar 

  4. Konig F. Ueber freie korper in den gelenken. Dtsch Z Chir. 1887;27:90–109.

    Article  Google Scholar 

  5. Aichroth P. Osteochondritis dissecans of the knee. A clinical survey. J Bone Joint Surg (Br). 1971;53(3):440–7.

    CAS  Google Scholar 

  6. Linden B. The incidence of osteochondritis dissecans in the condyles of the femur. Acta Orthop Scand. 1976;47:664–7.

    Article  CAS  PubMed  Google Scholar 

  7. Hefti F, Beguiristain J, Krauspe R, Moller-Madsen B, Riccio V, Tschauner C, Wetzel R, Zeller R. Osteochondritis dissecans: a multicenter study of the European Pediatric Orthopedic Society. J Pediatr Orthop B. 1999;8(4):231–45.

    CAS  PubMed  Google Scholar 

  8. Glancy GL. Juvenile osteochondritis dissecans. Am J Knee Surg. 1999;12:120–4.

    CAS  PubMed  Google Scholar 

  9. Gudas R, Simonaityte R, Cekanauskas E, Tamosiunas R. A prospective, randomized clinical study of osteochondral autologous transplantation versus microfracture for the treatment of osteochondritis dissecans in the knee joint in children. J Pediatr Orthop. 2009;29(7):741–8.

    Article  PubMed  Google Scholar 

  10. Cahill BR, Phillips MR, Navarro R. The results of conservative management of juvenile osteochondritis dissecans using joint scintigraphy. A prospective study. Am J Sports Med. 1989;17(5):601–5. discussion 605–606

    Article  CAS  PubMed  Google Scholar 

  11. Garrett JC. Fresh osteochondral allografts for treatment of articular defects in osteochondritis dissecans of the lateral femoral condyle in adults. Clin Orthop Relat Res. 1994;303:33–7.

    Google Scholar 

  12. Chambers HG, Shea KG, Carey JL. AAOS Clinical Practice Guideline: diagnosis and treatment of osteochondritis dissecans. J Am Acad Orthop Surg. 2011;19:307–9.

    Article  PubMed  Google Scholar 

  13. De Smet AA, Fisher DR, Graf BK, Lange RH. Osteochondritis dissecans of the knee: value of MR imaging in determining lesion stability and the presence of articular cartilage defects. AJR Am J Roentgenol. 1990;155:549–53.

    Article  PubMed  Google Scholar 

  14. De Smet AA, Ilahi OA, Graf BK. Reassessment of the MR criteria for stability of osteochondritis dissecans in the knee and ankle. Skelet Radiol. 1996;25(2):159–63.

    Article  Google Scholar 

  15. Kijowski R, Blankenbaker DG, Shinki K, Fine JP, Graf BK, De Smet AA. Juvenile versus adult osteochondritis dissecans of the knee: appropriate MR imaging criteria for instability. Radiology. 2008;248(2):571–8.

    Article  PubMed  Google Scholar 

  16. Cahill BR. Osteochondritis dissecans of the knee: treatment of juvenile and adult forms. J Am Acad Orthop Surg. 1995;3(4):237–47.

    Article  CAS  PubMed  Google Scholar 

  17. Wall EJ, Vourazeris J, Myer GD, Emery KH, Divine JG, Nick TG, et al. The healing potential of stable juvenile osteochondritis dissecans knee lesions. J Bone Joint Surg Am. 2008;90(12):2655–64.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Guhl JF. Arthroscopic treatment of osteochondritis dissecans. Clin Orthop Relat Res. 1982;167:65–74.

    Google Scholar 

  19. Lee CK, Mercurio C. Operative treatment of osteochondritis dissecans in situ by retrograde drilling and cancellous bone graft: a preliminary report. Clin Orthop Relat Res. 1981;158:129–36.

    Google Scholar 

  20. Johnson LL, Uitvlugt G, Austin MD, Detrisac DA, Johnson C. Osteochondritis dissecans of the knee: arthroscopic compression screw fixation. Arthroscopy. 1990;6(3):179–89.

    Article  CAS  PubMed  Google Scholar 

  21. Bradley J, Dandy DJ. Osteochondritis dissecans and other lesions of the femoral condyles. J Bone Joint Surg (Br). 1989;71:518–22.

    CAS  Google Scholar 

  22. Bruns J, Rayf M, Steinhagen J. Longitudinal long-term results of surgical treatment in patients with osteochondritis dissecans of the femoral condyles. Knee Surg Sports Traumatol Arthrosc. 2008;16:436–41.

    Article  PubMed  Google Scholar 

  23. Edmonds EW, Albright J, Bastrom T, Chambers HG. Outcomes of extra-articular, intra-epiphyseal drilling for osteochondritis dissecans of the knee. J Pediatr Orthop. 2010;30(8):870–8.

    Article  PubMed  Google Scholar 

  24. Larsen MW, Pietrzak WS, DeLee JC. Fixation of osteochondritis dissecans lesions using poly(L-lactic acid)/poly(glycolic acid) copolymer bioabsorbable screws. Am J Sports Med. 2005;33(1):68–76.

    Article  PubMed  Google Scholar 

  25. Michael JW, Wurth A, Eysel P, Konig DP. Long-term results after operative treatment of osteochondritis dissecans of the knee joint-30 year results. Int Orthop. 2008;32:217–21.

    Article  CAS  PubMed  Google Scholar 

  26. Prakash D, Learmonth D. Natural progression of osteo-chondral defect in the femoral condyle. Knee. 2002;9(1):7–10.

    Article  PubMed  Google Scholar 

  27. Bhosale AM, Richardson JB. Articular cartilage: structure, injuries and review of management. Br Med Bull. 2008;87:77–95.

    Article  PubMed  Google Scholar 

  28. Brittberg M, Lindahl A, Nilsson A, Ohlsson C, Isaksson O, Peterson L. Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. N Engl J Med. 1994;331(14):889–95.

    Article  CAS  PubMed  Google Scholar 

  29. Barry FP, Murphy JM. Mesenchymal ste cells: clinical applications and biological characterization. Int J Biochem Cell Biol. 2004;36(4):568584.

    Article  Google Scholar 

  30. Arinzeh TL. Mesenchymal stem cells for bone repair: preclinical studies and potential orthopaedic applications. Foot Ankle Clin. 2005;10(4):651–65.

    Article  PubMed  Google Scholar 

  31. Noel D, Djouad F, Jorgense C. Regenerative medicine through mesenchymal stem cells for bone and cartilage repair. Curr Opin Investig Drugs. 2002;3(7):1000–4.

    PubMed  Google Scholar 

  32. Caplan A. What are MSCs therapeutic? New data: new insight. J Pathol. 2009;217:318–24.

    Article  CAS  PubMed  Google Scholar 

  33. Im GI, Kim DY, Shin JH, Hyun CW, Cho WH. Repair of cartilage defect in the rabbit with cultured mesenchymal stem cells from bone marrow. J Bone Joint Surg (Br). 2001;83(2):289–94.

    Article  CAS  Google Scholar 

  34. Grigolo B, Lisignoli G, Desando G, Cavallo C, Marconi E, Tschon M, Giavaresi G, Fini M, Giardino R, et al. Osteoarthritis treated with mesenchymal stem cells on hyaluronan-based scaffold in rabbit. Tissue Eng Part C Methods. 2009;15:647–58.

    Article  CAS  PubMed  Google Scholar 

  35. Wakitani S, Imoto K, Yamamoto T, Saito M, Murata M, Yoneda M. Human autologous culture expanded bone marrow mesenchymal cell transplantation for repair of cartilage defects in osteoarthritic knees. Osteoarthr Cartil. 2002;10(3):199–206.

    Article  CAS  PubMed  Google Scholar 

  36. Saw KY, Anz A, Siew-Yoke Jee C, Merican S, Ching-Soong Ng R, Roohi SA, et al. Articular cartilage regeneration with autologous peripheral blood stem cells versus hyaluronic acid: a randomised controlled trial. Arthroscopy. 2013;29(4):684–94.

    Article  PubMed  Google Scholar 

  37. Freitag J, Ford J, Bates D, Boyd R, Hayne A, Wang Y, et al. Adipose derived mesenchymal stem cell therapy in the treatment of isolated knee chondral lesions: design of a randomised controlled pilot study comparing arthroscopic microfracture versus arthroscopic microfracture combined with postoperative mesenchymal stem cell injections. BMJ Open. 2015;5:e009332. doi:10.1136/bmjopen-2015-009332.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Peng L, Jia Z, Yin X, Zhang X, Liu Y, Chen P, Ma K, Zhou C. Comparative analysis of mesenchymal stem cells from bone marrow, cartilage, and adipose tissue. Stem Cells Dev. 2008;17(4):761–74.

    Article  CAS  PubMed  Google Scholar 

  39. Alvarez-Viejo M, Menendez-Menendez Y, Blanco-Gelaz MA, Ferrero-Gutierrez A, Fernandez-Rodriguez MA, Gala J, Otero-Hernandez J. Quantifying mesenchymal stem cells in the mononuclear cell fraction of bone marrow samples obtained for cell therapy. In Transplantation proceedings (Vol. 45, No. 1, pp. 434–439). Elsevier; 2013.

  40. Kern S, Eichler H, Stoeve J, Klüter H, Bieback K. Comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue. Stem Cells. 2006;24(5):1294–301.

    Article  CAS  PubMed  Google Scholar 

  41. Im GI, Shin YW, Lee KB. Do adipose tissue-derived mesenchymal stem cells have the same osteogenic and chondrogenic potential as bone marrow-derived cells? Osteoarthr Cartil. 2005;13:845–53.

    Article  PubMed  Google Scholar 

  42. Zuk PA, Zhu M, Mizuno H, Huang J, Futrell JW, Katz AJ, et al. Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng. 2001;7(2):211–28.

    Article  CAS  PubMed  Google Scholar 

  43. Martinello T, Bronzini I, Maccatrozzo L, Mollo A, Sampaolesi M, Mascarello F, et al. Canine adipose-derived-mesenchymal stem cells do not lose stem features after a long-term cryopreservation. Res Vet Sci. 2011;91(1):18–24.

    Article  CAS  PubMed  Google Scholar 

  44. Goh BC, Thirumala S, Kilroy G, Devireddy RV, Gimble JM, et al. Cryopreservation characteristics of adipose derived stem cells : maintenance of differentiation potential and viability. J Tissue Eng Regen Med. 2007;1(4):322–4.

    Article  CAS  PubMed  Google Scholar 

  45. Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, et al. Minimal Criteria for defining mulitpotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8(4):315–7.

    Article  CAS  PubMed  Google Scholar 

  46. Grodzinsky AJ, Levenston ME, Jin M, Frank EH. Cartilage tissue remodeling in response to mechanical forces. Annu Rev Biomed Eng. 2000;2(1):691–713.

    Article  CAS  PubMed  Google Scholar 

  47. Messingham MJ, Arpey CJ. Update on the use of antibiotics in cutaneous surgery. Dermatol Surg. 2005;31(8 Pt 2):1068–78.

    CAS  PubMed  Google Scholar 

  48. Roos EM, Roos HP, Lohmander LS, Ekdahl C, Beynnon BD. Knee Injury and Osteoarthritis Outcome Score (KOOS)-development of a self-administered outcome measure. J Orthop Sports Phys Ther. 1998;28(2):88–96.

    Article  CAS  PubMed  Google Scholar 

  49. Bellamy N, Buchanan WW, Goldsmith CH, Campbell J, Stitt LW. Validation study of WOMAC: a health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee. J Rheumatol. 1988;15(12):1833–40.

    CAS  PubMed  Google Scholar 

  50. Dworkin RH, Turk DC, Farrar JT, Haythornthwaite JA, Jensen MP, Katz MP, et al. Core outcome measures for chronic pain clinical trials: IMMPACT recommendations. Pain. 2005;113:1–2.

    Article  Google Scholar 

  51. Brittberg M, Winalski CS. Evaluation of cartilage injuries and repair. J Bone Joint Surg Am. 2003;85-A(Suppl 2):58–69.

    Article  Google Scholar 

  52. Mamisch TC, Trattnig S, Quirback S, Marlovits S, White LM, Welsch GH. Quantitative T2 mapping of knee cartilage: differentiation of healthy control cartilage and cartilage repair tissue in the knee with unloading- initial results. Radiology. 2010;254(3):818–26.

    Article  PubMed  Google Scholar 

  53. Crema MD, Roemer FW, Marra MD, Burstein D, Gold GE, Eckstein F, Baum T, Mosher TJ, Carrino JA, Guermazi A. Articular Cartilage in the Knee: Current MR Imaging Techniques and Applications in Clinical Practice and Research 1. Radiographics. 2011;31(1):37–61.

    Article  PubMed  Google Scholar 

  54. Spaková T, Rosocha J, Lacko M, Harvanova D, Gharaibeh A. Treatment of knee joint osteoarthritis with autologous platelet-rich plasma in comparison with hyaluronic acid. Am J Phys Med Rehabil. 2012;91(5):411–7.

    Article  PubMed  Google Scholar 

  55. Kon E, Mandelbaum B, Buda R, Filardo G, Delcogliano M, Timoncini A, et al. Platelet-rich plasma intra-articular injection versus hyaluronic acid viscosupplementation as treatments for cartilage pathology: from early degeneration to osteoarthritis. Arthroscopy. 2011;27(11):1490–501.

    Article  PubMed  Google Scholar 

  56. Freitag JB, Barnard A. To evaluate the effect of combining photo-activation therapy with platelet-rich plasma injections for the novel treatment of osteoarthritis. BMJ Case Rep. 2013;26:2013. doi:10.1136/bcr-2012-007463.

    Google Scholar 

  57. Mascarenhas R, Saltzman BM, Fortier LA, Cole BJ. Role of platelet-rich plasma in articular cartilage injury and disease. J Knee Surg. 2015;28(1):3–10.

    Article  PubMed  Google Scholar 

  58. Peterson L, Minas T, Brittberg M, Nilsso A, Sjogren-Jansson E, Lindahl A. Two- to 9-year outcome after autologous chondrocyte transplantation of the knee. Clin Orthop Relat Res. 2000;374:212–34.

    Article  Google Scholar 

  59. Ahsan T, Lottman LM, Harwood F, Amiel D, Sah RL. Integrative cartilage repair: inhibition by beta-aminopropionitrile. J Orthop Res. 1999;17(6):850–7.

    Article  CAS  PubMed  Google Scholar 

  60. von der Mark K, Gauss V, von der Mark H, Muller P. Relationship between cell shape and type of collagen synthesized as chondrocytes lose their cartilage phenotype in culture. Nature. 1977;267:531–2.

    Article  PubMed  Google Scholar 

  61. Marlovits S, Hombauer M, Truppe M, Vessei V, Schlegel W. Changes in the ratio of type-I and type-II collagen expression during monolayer culture of human chondrocytes. J Bone Joint Surg (Br). 2004;86(2):286–95.

    Article  CAS  Google Scholar 

  62. Jing XH, Yang L, Duan XJ, Xie B, Chen W, Li Z, Tan HB. In vivo MR imaging tracking of magnetic iron oxide nanoparticle labeled, engineered, autologous bone marrow mesenchymal stem cells following intra-articular injection. Joint Bone Spine. 2008;75(4):432–8.

    Article  PubMed  Google Scholar 

  63. Mokbel AN, El Tookhy OS, Shamaa AA, Rashed LA, Sabry D, El Sayed AM. Homing and reparative effect of intra-articular injection of autologus mesenchymal stem cells in osteoarthritic animal model. BMC Musculoskelet Disord. 2011;12(1):1.

    Article  Google Scholar 

Download references

Acknowledgements

The authors would like to acknowledge the following people for their contribution to the case study.

 -- Dr Paul Marks and Dr Chris Holden (Radiologists at Imaging Associates) for radiological analysis.

 -- Dr Dan Bates and Dr Leesa Huguenin for assistance in development of the treatment protocol.

 -- Dr Adele Barnard (Research Fellow at Clinical Intelligence) and Renee Castelluccio for assistance in data acquisition.

Funding

No funding was obtained for the purpose of this study.

Availability of data and materials

All data generated or analysed during this study are included in this published article.

Author information

Authors and Affiliations

  1. Charles Sturt University, NSW, Australia

    Julien Freitag & James Wickham

  2. Magellan Stem Cells, VIC, Australia

    Kiran Shah

  3. The Hudson Institute, Victoria, Australia

    Richard Boyd

  4. Monash University, VIC, Australia

    Abi Tenen

Authors
  1. Julien Freitag
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kiran Shah
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. James Wickham
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Richard Boyd
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Abi Tenen
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

JF, RB, KS were involved in the conception and design of the study. JF, RB, AT, JW, KS were involved in the drafting of the report. JF, RB, AT, JW, KS have read and approved the final manuscript.

Corresponding author

Correspondence to Julien Freitag.

Ethics declarations

Ethics approval and consent to participate

he subject was formally enrolled in a prospective ethics approved case series. The subject completed formal informed consent prior to commencement of the study. Monash University Human Research Ethics Committee Number: CF14/2230–2014001175.

Consent for publication

The subject within this case study has formally consented to publication of details pertaining to their treatment and outcome.

Competing interests

Dr Julien Freitag and Professor Richard Boyd are affiliated with Magellan Stem Cells and are members of Magellan Stem Cells Clinical and Scientific Advisory Board. Dr Kiran Shah is the Chief Scientific Officer of Magellan Stem Cells.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Freitag, J., Shah, K., Wickham, J. et al. The effect of autologous adipose derived mesenchymal stem cell therapy in the treatment of a large osteochondral defect of the knee following unsuccessful surgical intervention of osteochondritis dissecans – a case study. BMC Musculoskelet Disord 18, 298 (2017). https://doi.org/10.1186/s12891-017-1658-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s12891-017-1658-2

Keywords

BMC Musculoskeletal Disorders

ISSN: 1471-2474

Contact us