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Stem cell harvest and transplant for knee osteochondral defect (Synergy Medical technologies)

    Overview

    Professional Guidelines Included
    Learn the Stem cell harvest and transplant for knee osteochondral defect (Synergy Medical technologies) surgical technique with step by step instructions on OrthOracle. Our e-learning platform contains high resolution images and a certified CME of the Stem cell harvest and transplant for knee osteochondral defect (Synergy Medical technologies) surgical procedure.
    Osteochondral defects (OCDs) of the knee are a relatively common problem and can be challenging to treat. Articular cartilage is avascular and consequently has limited regenerative potential. The avascularity is speculated to limit progenitor cell infiltration, which is necessary for cartilage regeneration. Adequate treatment of OCDs is essential to prevent progressive tissue loss and ultimately degenerative joint disease.
    Traditional methods of treatment such as microfracture or mosaicplasty are generally reserved for smaller defects (i.e. < 2 cm2) and result in fibrocartilage formation, which has inferior biomechanical and biochemical properties to hyaline cartilage and over time undergoes degeneration.
    The use of a cellular repair (autologous chondrocyte implantation) is not new but recently became a NICE (National Institute for Clinical Excellence) recommended procedure in the UK. It involves two stages and laboratory culture of harvested chondrocyte cells.
    This ‘stem cell harvest and transplant’ technique uses chondrocyte precursor cells (mesenchymal stem cells) harvested from the pelvis and has the advantage of being performed in a single stage; it is also cheaper than ACI. We have performed this at our institution for over 4 years and have demonstrated significant improvements in Cincinatti scores at two years. The three year graft survival is 96.3%. Poorer results are found in older patients and those who have had previous surgery.
    Rehabilitation is crucial and return to sports is not expected before the six month mark.
    The ‘Syngenit surgical’ kit is produced by Synergy Medical Technologies, UK. It comes sterile packed in one box and is based on a similar technique published by Buda et al at the Rizzolli Institute (Buda et al. J Bone Joint Surg Am 2010;92 [Suppl. 2]:2–11). They successfully used a hyaluronic acid membrance and 2mls of concentrated bone marrow aspirate for knee articular cartilage repair.
    Readers will also find of interest the following related OrthOracle techniques:
    Knee arthroscopy and microfracture of osteochondral defect
    Osteochondral grafting of the talus (OATS procedure)
    Clinicians should seek clarification on whether any implant demonstrated is licensed for use in their own country.
    In the USA contact: https://www.fda.gov/medical-devices/products-and-medical-procedures
    In the UK contact: https://www.gov.uk/government/organisations/medicines-and-healthcare-products-regulatory-agency
    In the EU contact: https://www.ema.europa.eu/en/human-regulatory/overview/medical-devices

    Indications

    INDICATIONS
    Stem cell transplantation is indicated for isolated osteochondral defects of the knee over 2 square centimetres in size in symptomatic, motivated patients between 15 and 55 years of age. There is no upper size limit as long as the defect is surrounded by normal articular cartilage. In large cavitatory lesions (deeper than 8-10mm) bone graft may also be required. I prefer autologous bone and make a window in the non-articulating part of the medical femoral condyle and harvest from there. Allograft chips can also be used where less volume is required. If further filling of the defect is needed a collagen bilayer can be created by doubling up the implanted collagen membrane, similar to the MACI ‘sandwich’ technique.
    Best results are observed in younger patients – this likely reflects both the decreased reparative potential and probable subclinical osteoarthritis with age. Previous surgery, especially microfracture, is a negative prognostic factor. There doesn’t seem to be a difference in outcome between sex, lesion size, lesion location and site of cell harvest (anterior or posterior pelvis).
    The knee should be mechanically stable with normal alignment. Where there is malalignment, either tibiofemoral or patellofemoral, this needs to be corrected concurrently; the same applies for ligamentous instability and ligament reconstruction can be performed at the same time. About 10% of patients need a concurrent procedure.
    In 2017 NICE published guidance on the use of ACI (autologous chondrocyte implantation) and the same guidance applies to the this procedure. Their guidance suggests the following criteria are met when considering the technique.
    The person has not had previous surgery to repair articular cartilage defects
    There is minimal osteoarthritic damage to the knee
    The defect is over 2 cm2
    The procedure is done at a tertiary referral centre.
    SYMPTOMS & EXAMINATION
    Patients usually complain of pain, swelling, locking, instability and loss of function. Most patients are young and may have restrictions in day to day activities and sports.
    A thorough knee examination is crucial to both localise the pathology (tenderness) and assess the rest of the joint. The presence of an effusion, quadriceps bulk, range of movement and alignment can be observed. Ligamentous stability both in the sagittal and coronal planes must be tested. If the lesion is in the patellofemoral compartment care must be taken to identify patella height, tracking and crepitus.
    IMAGING
    Plain radiographs including AP, lateral and skyline views are helpful in assessing the bony morphology as well as more generalised joint degeneration.
    Long alignment radiographs are needed if malalignment is suspected and a corrective osteotomy is considered as part of the joint preserving management.
    An MRI scan is mandatory to confirm the OCD size and location, as well as confirm the examination findings. The imaging (combined with the history and examination findings) may determine the necessity for a concurrent procedure to address malalignment or ligamentous deficiency.
    The MRI scan also gives an idea on the severity of the OCD. There is no widely accepted classification system and the ones that are used vary according to the aetiology. Osteochondral defects are conventionally described using the International Cartilage Repair Society score, with a higher score correlating with worse prognosis. It was however designed for arthroscopic assessment and not MRI. Grade 0 is normal cartilage, grade 1 is soft (1a) or demonstrates superficial fissures and cracks (1b); grade 2 has defects less than 50% of the cartilage depth; grade 3 has defects greater than 50%, and this is further classified into a, b, c and d. Grade 4 is severely abnormal bone with penetration through the subchondral bone. More recently an AMADEUS (Area Measurement And DEpth & Underlying Structures) scoring system has been designed as an MRI score and classification system (Jungmann et al, Cartilage 2017) but it is not in common use.
    ALTERNATIVE OPERATIVE TREATMENT
    Microfracture is the most commonly performed alternative but the fibrocartilaginous repair is biomechanically inferior to either hyaline-like or hyaline cartilage. Improvements of the microfracture technique include the use of a membrane or non-cellular implant after marrow stimulation eg. autologous matrix induced chondrogenesis, Chondrotissue.
    Mosaicplasty is another, less common, alternative whereby cylindrical plugs of bone and cartilage are harvested and transplanted.
    ACI is a cellular alternative and NICE approved but involves two stages – one to harvest the cells and the second for implantation. It is also expensive and the lack of commercial laboratories in the UK has limited its use in recent years.
    NON-OPERATIVE MANAGEMENT
    Physical therapy, activity modification and analgesia are the mainstay. In less active and older patients this may be enough to keep the symptoms under control.
    CONTRAINDICATIONS
    Inflammatory arthropathy
    Advanced osteoarthritic change
    Malalignment on instability
    Obesity
    Smoking
    Patient likely to be non-compliant with post-operative regime
    Previous surgery for cartilage repair

    Setup

    The procedure is performed under general anaesthetic, usually with a femoral or adductor canal nerve block.
    A diagnostic knee arthroscopy may be performed prior to bone marrow harvest to confirm the OCD and to exclude any other intra-articular pathology, but is often not necessary with up-to-date high-resolution cross-sectional imaging.
    Bone marrow may be harvested from the posterior superior iliac spine with the patient in the lateral decubitus position using a powered bone marrow aspiration system or a Jamshidi needle. Alternatively bone marrow may be harvested from the anterior superior iliac spine with the patient remaining in a supine position. This negates the need for turning the patient in order to re-prep and drape and is my preferred technique. The quantity and quality of the harvested stem cells is not effected and the procedure is more streamlined.
    For convenience I prep and drape both the leg and the ipsilateral anterior superior iliac spine at the same time. A hole can be made in the drapes to access the pelvis for the bone marrow aspiration.

    Operation – 1

    The pre-op coronal T1 images of a medial femoral condyle osteochondral defect.
    Chronic osteochondral defect with evidence of previous failed fixation, 1. Note the lack of the normal dark grey cartilage layer in the effected area.

    Coronal MRI of the same patient’s knee at 6 months post stem cell transplantation shows good in-filling of the osteochondral defect,1.

    The posterior aspect of the ASIS is the thickest and usually easiest to accessA small stab incision is made in the skin over the anterior superior iliac spine. The trocar needle and cannula assembly are then introduced and advanced. The anterior and posteriod aspect of the crest can be felt with the trocar tip and the midpoint chosen for the needle entry.
    While holding the trocar assembly in the palm, gentle but firm pressure will advance the needle, rotating it in an alternating clockwise/counter clockwise motion until it advances between the cortices of the iliac crest. In general, advance the trocar no more than 5cm.
    The direction may vary depending on the patient’s body habitus, position and the precise entry point.

    A Jamshedi needle is inserted into the anterior superior iliac spineThe posterior aspect of the anterior superior iliac spine is palpated and the needle inserted and advanced. Care is needed to avoid slipping anteriorly as there is a theoretical risk of a visceral or neurovascular injury.
    Bone marrow harvest is generally rapid but does depend on the patient’s age and hydration status.

    Heparinised syringes are used to aspirate 60mls of bone marrow.The aspirate is taken in 5ml aliquots with re-positioning of the needle tip each time. This is to ensure the best cellular content of the aspirate and reduce dilution with peripheral blood.

    The aspirated bone marrow is collected in a sterile bag.The scrub nurse takes each syringe and injects it into the sterile heparinised bag. 60mls is ideal but the procedure can be run using 40mls at the minimum.

    Local anaesthetic is administered into the periosteum and soft tissues before closure with steristrips.

    Remaining in a sterile heparinised environment the aspirate is transferred to a large syringe

    The syringe is attached to the centrifuge (Autospin bone marrow concentration system)
    The cells are centrifuged in the operating theatre. The consumables are single use and sterile-packed but the machine itself is not sterile and outside of the operating field.
    The cycle time is approximately 17 minutes. A spin speed of approximately 2800 RPM.

    Density centrifugation is a simple method to separate anticoagulated blood. It relies on the principle of varying cell densities within a heterogeneous sample.

    The mononuclear cells (monocytes) are less dense than other cell types and a concentrated (2-3ml) sample is produced from a 60 ml bone marrow sample that contains high numbers of bone marrow derived mesenchymal stem cells, the ones required for this technique.

    The centrifuged cells are aspirated into a syringe and brought back into the operating field.

    A mini-arthrotomy is performed to access the knee, the skin incision depends on the location of the chondral defect.A tourniquet is inflated and the knee is accessed via a mini-arthrotomy.
    The skin incision depends on the location of the chondral defect.
    An anteromedial incision can be used for a medial parapatellar approach to access the medial compartment and patellofemoral compartment.
    An anterolateral incision is needed for a lateral parapatellar approach to access the lateral compartment.
    Beneath the extensor mechanism the capsule needs to be identified and the knee joint entered carefully to avoid damaging healthy articular cartilage. This is often easier with the knee extended. The anterior horns of the medial or lateral meniscii are potentially at risk.
    The incision need only be a few cm in length as flexion and extension of the knee will bring the defect into view.

    A self retainer is carefully inserted and the chondral defect defined.
    1. Laterally displaced patella
    2. Fat pad
    3. Chondral defect on the medial femoral condyle

    Once the joint is open the damaged cartilage is removed if it is still present

    If the osteochondral fragment has become separated it will need to be found and removed.

    A sharp scalpel is used to precisely cut the junction between the defective cartilage and the healthy surrounding cartilage.Sharp dissection is used to minimise injury to the surrounding healthy tissue.

    The subchondral bone should ideally be left alone. If however the osteochondral defect is deep and requires bone graft this is the time to prepare it.The defect needs to be prepared to ensure it has vertical edges all the way around and is surrounded by normal healthy articular cartilage. This will help keep the collagen scaffold in place and allow the best chance of integration of the graft with normal articular cartilage.
    The subchondral bone should ideally be left alone. If however the osteochondral defect is deep and requires bone graft this is the time to prepare it. Osteophytes and sclerotic bone are removed with a gouge or bone nibbler and either auto- or allograft bone is inserted to reconstitute the bony anatomy.
    My preference for deep lesions (>8mm) is to use cancellous autograft taken from a window made in the non-articulating part of the medial femoral condyle. The window allows access to good quality cancellous bone and can be secured at the end with the same ‘fibrin’ glue that is used to secure the stem cell graft.

    A template is used to mark out the defect size and shapeA type 1 collagen sponge is used as a scaffold. This must be cut to fill the defect – I use the metal foil cover that comes with the sponge as a template and cut this to the required shape.

    A type one equine collagen scaffold is then cut to size to match the template producedThe scaffold needs to be seated into the defect and not proud of the surrounding cartilage. Two thicknesses of collagen sponge are provided in the kit, which in the majority of patients is adequate. If the defect is deep bone can be used as explained earlier. Alternatively the collagen scaffold can be ‘doubled up’ and inserted one layer on top of another, with or without bone graft deep to it.
    The scaffold comes as a sterile commercial product (Syngenit Biomatrix). It has a multi-dimensional crosslink structure allowing maximum porosity for potential chondrocyte cell seeding.

    The concentrated mesenchymal stem cells are soaked on to the scaffoldThe scaffold is soaked with the stem cells for two minutes. Using sterile forceps, the membrane may be turned over to ensure full saturation.

    Real time cell analysisA sample of the aspirate is taken to calculate the cell numbers using a Muse (Merck) cell analyser. This provides real-time feedback on mesenchymal stem cell number and viability. The cell count generally varies between approximately 7 × 107 and 4 × 108 depending on the aspiration technique and the number of nucleated cells in the bone marrow aspirate, which is patient-dependent.

    The scaffold soaked with stem cells is implanted into the chondral defect ensuring it covers the defect and is not proud of the surrounding articular surface.

    The soaked collagen scaffold should fill the defect as much as possible. It is pliable and can be manipulated to achieve this. Vertical edges are ideal but not always possible, particularly with medial femoral condyle defects near the intercondylar notch or with peripheral patella defects.
    Stem cell soaked collagen scaffold
    Surrounding articular cartilage

    Preparation of the autologous fibrin ‘glue’The collagen scaffold needs to be secured in place. Historically, and with ACI, this was achieved using a commercially available fibrin sealant (Tisseel).
    One modification I now use is the use of autologous fibrin. It contains numerous growth factors (TGF-beta, PDGF-AB, bFGF, IGF, VEGF, EGF) which are released as the fibrin matrix is degraded. This (hopefully) stimulates fibroblast proliferation, collagen synthesis and offers some protection against proteolytic degradation.
    The autologous fibrin glue is prepared at the same time as the scaffold insertion in a similar manner to the preparation of platelet rich plasma.
    Thirty millilitres of the patient’s blood is placed into three vactubes. Two of the vactubes contain anticoagulant citrate dextrose solution (ADCA), which is used to produce fibrinogen. The third does not and produces a clot which releases thrombin serum.

    Operation – 2

    The vacutubes are centrifuged at a speed of 3500 RPM. The processing time is five minutes for tubes containing ADCA (fibrinogen production) and 10 min for the non-ACDA tube (thrombin serum production).

    The fibrinogen and thrombin serum are aseptically transferred into the sterile field and the thrombin serum is combined with 0.5 mL of calcium gluconate to act as a source of calcium ions.

    The ‘fibrin glue’ is produced when the thrombin and fibrinogen are mixed together. This both creates a niche microenvironment for cartilage regeneration and secures the collagen scaffold in place.

    Fibrin formation.
    The final part of the clotting cascade: thrombin activates fibrinogen, which in the presence of calcium produces fibirn.

    The thrombin and fibrinogen are mixed, creating fibrin. This is injected and positioned around the scaffold edges to secure it in place.

    The material transitions from a low viscosity to a dense fibrinogen membrane over a period of several minutes, which is patient-dependent. The process is accelerated when the material comes into contact with the Type 1 collagen membrane and bone marrow aspirate.

    Once fixation has been achieved the knee is gently cycled between flexion and extension to confirm that the implant is stable and not impinging on other structures. If not, it is re-assessed and / or re-positioned.


    The knee joint and subcutaneous tissues are then closed with 1 vicryl to the capsule and extensor mechanism, 2/0 vicryl and monocryl to the skin.

    Local anaesthetic infiltration to the soft tissues
    20mls of 0.5% chirocaine is injected in to the soft tissues.

    Steristrips, dressing and a compression bandage are applied before an extension brace is fitted.

    Sagittal views of a similar osteochondral defect
    Pre-op. An osteochondral defect is visible with underlying bone marrow oedema
    Resolution of the bone marrow oedema and a hyaline like cartilage repair at 6 months post-op.

    Post Operative

    The knee is locked in an extension brace for the first week postoperatively.
    Range of movement exercises then begin after one week. Closed chain active or active-assisted range of movement knee flexion and extension, closed chain quadriceps, stationary quadriceps, co-contraction of the quadriceps and hamstrings and low resistance isometric exercises are commenced. Stationary cycling, with low resistance, may be introduced from week four postoperatively as tolerated.
    For patellar or trochlear grafts, patients are allowed to fully weight bear immediately with the knee locked in extension for four weeks.
    Range of movement exercises are commenced from 0 to 90 degrees of flexion until four weeks postoperatively.
    From four to six weeks, the brace is unlocked gradually for weight-bearing as control allows, with the aim of not wearing the brace from six weeks postoperatively.
    For femoral condyle or tibial plateau grafts, patients may bear weight with the protection of crutches for six weeks and progress with range of movement as symptoms allow, aiming for full range of movement at six weeks. Patients can be weaned from the brace at six weeks as control allows. After six weeks, when normal movement has returned, physiotherapy is directed at improving strength and balance/proprioception. This includes the introduction of resistance work with bands or weights. The aim is to return to all activities including full participation in sports by six months postoperatively.
    Potential complications include stiffness (requiring manipulation under anaesthesia), graft overgrowth (requiring arthroscopic debridement) or failure.

    Recommended Reading

    Bone marrow aspirate and stem cell transplantation is a relatively novel technique, which remains in its infancy. There are clear advantages in regenerating articular cartilage with only one procedure and at a cost saving compared with ACI. There is limited clinical data on outcomes following stem cell transplantation; at our institution the first 100 cases with two year clinical outcome data have been presented (BASK 2019) and show a similarly significant improvement to conventional ACI. Our current two year results are in press.
    The current NICE guidance from 2017, Autologous chondrocyte implantation for treating symptomatic articular cartilage defects of the knee, https://www.nice.org.uk/guidance/ta477, recommends ACI as an option for treating symptomatic chondral defects of the knee only if the patient has not had previous cartilage reparative surgery, based on evidence that ACI is likely to be more successful as a first-line surgical treatment. Previous reports or case series of stem cell transplantation of the knee have also focused on using this as a first-line treatment. Therefore, this suggests that the major role of stem cell transplantation is as a first-line treatment.
    Previous microfracture has been associated with a three times greater failure rate of ACI (Minas et al. Clin Orthop Relat Res. 2001). Our preliminary results suggest the same with previous cartilage surgery, in particular microfracture, a negative prognostic factor. The other most important negative predictor in our cohort of patients is age, with less improvement observed as age increases.
    Bone marrow aspirate and stem cell transplantation is a relatively novel technique, which remains in its infancy. There are clear advantages in regenerating articular cartilage with only one procedure and at a cost saving compared with ACI. There is limited clinical data on outcomes following stem cell transplantation; at our institution the first 100 cases with two year clinical outcome data have been presented (BASK 2019) and show a similarly significant improvement to conventional ACI. Our current two year results are in press.
    The current NICE guidance from 2017, Autologous chondrocyte implantation for treating symptomatic articular cartilage defects of the knee, https://www.nice.org.uk/guidance/ta477, recommends ACI as an option for treating symptomatic chondral defects of the knee only if the patient has not had previous cartilage reparative surgery, based on evidence that ACI is likely to be more successful as a first-line surgical treatment. Previous reports or case series of stem cell transplantation of the knee have also focused on using this as a first-line treatment. Therefore, this suggests that the major role of stem cell transplantation is as a first-line treatment.
    Previous microfracture has been associated with a three times greater failure rate of ACI (Minas et al. Clin Orthop Relat Res. 2001). Our preliminary results suggest the same with previous cartilage surgery, in particular microfracture, a negative prognostic factor. The other most important negative predictor in our cohort of patients is age, with less improvement observed as age increases.
    Haleem et al. Cartilage 2010;1:253–261
    Haleem reported a technique where autologous bone marrow-derived stem cells were culture-expanded and transplanted in femoral condyle chondral defects. Their technique differed from the technique described in this paper as they harvested only 20 mL of bone marrow from the iliac crest and due to the low stem cell numbers obtained, culture-expansion was required, thus necessitating a two-stage technique.
    Buda et al. J Bone Joint Surg (Am) 2010;92 [Suppl. 2]:2–11.
    Buda reported a single-stage technique using a hyaluronic acid membrane filled with 2 mL of an autologous bone marrow concentrate. Their case series included patients with either medial or lateral femoral condyle defects, in contrast to ours where condylar and patellofemoral defects are both addressed (with re-alignment if necessary). Their technique also involved harvesting of blood pre-operatively the day before surgery to provide platelet-rich fibrin gel, whereas our technique involves fibrin gel being obtained from blood taken from the patient intra-operatively. They also performed the procedure arthroscopically whereas we believe a mini-arthrotomy is necessary to accurately debride the defect and to ensure secure fixation with fibrin glue. It is unclear if this may have accounted for the fact that Buda et al.’s postoperative rehabilitation schedule involved starting full weight-bearing and exercises focusing on recovery of muscular function at 10 weeks postoperatively, compared with our accelerated rehabilitation programme with these activities being commenced after the first postoperative week. This is considered important as many of our patients are young active patients and compliance with a more lengthy rehabilitation programme may be variable.
    Further reading for a general synopsis of treating chronic articular defects in the knee:
    Current solutions for the treatment of chronic articular cartilage defects in the knee. M Chimutengwende-Gordon, J Donaldson, G Bentley. EFORT Open Rev 2020;5:156-163. DOI: 10.1302/2058-5241.5.190031

    Reference

    • orthoracle.com

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