Spherox: Uses, Dosage & Side Effects
An autologous cell-based advanced therapy for the repair of symptomatic articular cartilage defects of the knee in adult patients
Spherox is a prescription-only advanced therapy medicinal product (ATMP) used to repair symptomatic cartilage defects of the femoral condyle and patella of the knee in adult patients. It consists of three-dimensional spheroids of the patient's own (autologous) chondrocytes grown together with their self-produced extracellular matrix. After a cartilage biopsy during an initial arthroscopy, cells are expanded in a specialized laboratory over approximately 6–8 weeks and delivered back to the surgeon as a ready-to-implant suspension. During a second, definitive procedure, 10–70 spheroids per cm² are applied directly into the debrided defect, where they self-adhere within about 20 minutes without the need for glue, membrane or suture. The repair tissue matures gradually over 6–24 months into hyaline-like cartilage, with clinical improvement in pain and knee function demonstrated through randomized controlled trials and sustained at 5 years of follow-up.
Quick Facts: Spherox
Key Takeaways
- Spherox is an autologous cell therapy that uses three-dimensional spheroids of the patient's own chondrocytes to repair localized cartilage defects of the femoral condyle and patella of the knee in adult patients.
- It is indicated for symptomatic, focal cartilage defects classified as ICRS grade III or IV with a defect area of up to 10 cm². It is not a treatment for generalized osteoarthritis or for defects in skeletally immature patients.
- Treatment requires two surgical procedures: an initial arthroscopic cartilage biopsy followed 6–8 weeks later by implantation of the cultured spheroid product at 10–70 spheroids per cm² of defect area.
- Randomized controlled trials and long-term follow-up demonstrate significant improvements in pain, knee function (IKDC, KOOS) and quality of life sustained for at least 5 years, with outcomes comparable or superior to microfracture.
- Most side effects are related to knee surgery (joint effusion, pain, stiffness, cartilage hypertrophy, bone marrow oedema) rather than the cells themselves; serious complications are uncommon and structured rehabilitation is essential to outcome.
What Is Spherox and What Is It Used For?
Spherox is a tissue-engineered medicinal product classified by the European Medicines Agency as an advanced therapy medicinal product (ATMP). It belongs to the category of autologous cell therapies, meaning it uses cells taken from the patient's own body. The active substance consists of spheroids — small, three-dimensional aggregates of chondrocytes (the cells that form cartilage) together with the extracellular matrix these cells have synthesized during culture. Each spheroid typically contains around 200,000 chondrocytes arranged in a densely packed, cartilage-like microtissue. Spherox was granted European marketing authorization in July 2017 and is used in specialized orthopedic centers across Europe.
The approved indication for Spherox is the repair of symptomatic articular cartilage defects of the femoral condyle or the patella of the knee in skeletally mature adults. The defect must be classified as grade III (deep partial-thickness lesions extending more than 50% of the cartilage depth) or grade IV (full-thickness lesions reaching or breaching the subchondral bone) according to the International Cartilage Repair Society (ICRS) grading system. The defect size for which clinical data exist is up to 10 cm². Spherox is not a treatment for generalized osteoarthritis, for patients with advanced multi-compartmental joint degeneration, or for children whose growth plates have not yet closed.
Articular cartilage has very limited capacity to heal spontaneously because it is avascular (has no blood supply), aneural, and contains a sparse population of specialized cells. Even small, traumatic cartilage injuries can enlarge over time, disturb joint biomechanics, and eventually lead to pain, stiffness, mechanical symptoms (locking, catching) and, if untreated, secondary osteoarthritis of the knee. Focal cartilage injuries typically occur after sports trauma, work-related injuries, osteochondritis dissecans, or repetitive impact loading. Many patients affected by these lesions are relatively young — often between 20 and 50 years old — and wish to preserve their natural joint rather than proceed to a total knee replacement.
Traditionally, surgical options for focal cartilage defects include marrow-stimulation techniques such as microfracture, subchondral drilling and nanofracture, osteochondral autograft transplantation (OATS or mosaicplasty), osteochondral allografts, and cell-based therapies such as autologous chondrocyte implantation (ACI) or matrix-associated ACI (MACI). Third-generation cell therapies like Spherox represent a refinement of the ACI concept: rather than implanting a cell suspension or a cell-seeded membrane, the surgeon applies self-adhering spheroids of cartilage tissue directly into the debrided defect. This approach removes the need for periosteal flap harvesting, suturing, fibrin glue, or synthetic scaffolds, and is designed to produce more homogeneous, hyaline-like repair tissue.
Mechanistically, once the spheroids are applied to the prepared cartilage defect, they adhere to the exposed subchondral bone and surrounding cartilage rim within approximately 20 minutes through natural adhesion molecules on the spheroid surface. Chondrocytes then migrate out of the spheroid structure, proliferate at the defect site, and deposit new extracellular matrix rich in type II collagen and sulfated proteoglycans (aggrecan) — the hallmarks of functional hyaline cartilage. Over 6 to 24 months the defect gradually fills with repair tissue that progressively matures in composition and mechanical properties. Magnetic resonance imaging (MRI) at serial time-points confirms progressive filling, integration with adjacent cartilage, and improvement of the subchondral bone plate.
The pivotal clinical evidence for Spherox comes from two prospective, multicenter, randomized controlled trials and long-term extension studies:
- Phase II dose-ranging trial (CS-ATMP-02): A randomized controlled trial comparing three different doses of Spherox (3–7, 10–30, and 40–70 spheroids per cm²) in 75 adult patients with cartilage defects of the knee (4–10 cm²). All three dose groups achieved clinically meaningful and statistically significant improvements in pain and function on the International Knee Documentation Committee (IKDC) subjective score and the Knee injury and Osteoarthritis Outcome Score (KOOS), with no clear dose-response and a similar safety profile across groups. Results were sustained at 60-month follow-up.
- Phase III pivotal trial (CS-ATMP-03): A randomized, active-controlled trial comparing Spherox with microfracture in 114 adult patients with cartilage defects of 1–4 cm². After 24 months, Spherox showed non-inferiority to microfracture on the KOOS composite endpoint, with a trend toward improved durability of response in the Spherox arm at 5-year follow-up, particularly in defects larger than 2 cm².
Across studies, the most consistent findings are progressive reduction in knee pain, improved ability to perform activities of daily living and recreational sports, and good-to-excellent filling of the defect on post-operative MRI using the MOCART (Magnetic Resonance Observation of Cartilage Repair Tissue) scoring system. Outcomes are best when defects are smaller, treated earlier after symptom onset, isolated (single lesion), located on the femoral condyle, and when concomitant factors such as limb malalignment, meniscal deficiency or ligamentous instability have been corrected.
The best candidates are adults (skeletally mature, typically 18–50 years old) with a single, well-defined, focal ICRS grade III or IV cartilage lesion of the femoral condyle or patella, a defect size of 1–10 cm², intact menisci and ligaments (or surgically correctable), neutral lower-limb alignment (or correctable with osteotomy), a BMI typically below 30–35 kg/m², and realistic expectations with willingness to commit to an intensive 9–12 month rehabilitation programme.
What Should You Know Before Taking Spherox?
Contraindications
Spherox must not be used in the following situations. The product must not be implanted if the patient is hypersensitive to any component of the product or the excipients used in the suspension medium. It must not be used in patients with advanced osteoarthritis of the knee (ICRS osteoarthritis grade III or IV, or Kellgren-Lawrence grade 3–4 on weight-bearing radiographs), because the surrounding cartilage environment is no longer competent to integrate and protect the new repair tissue. It must also be avoided in patients with active inflammatory joint disease (such as rheumatoid arthritis, psoriatic arthritis or crystal arthropathy affecting the target knee), active bacterial or viral infection of the joint or adjacent soft tissues, and in patients whose growth plates in the femur or tibia have not yet closed.
Further contraindications include known chronic blood-borne infections that would pose a risk to the manufacturing process or to the patient, including HIV, active hepatitis B or C, and syphilis. Pre-implantation screening of the original biopsy tissue is mandatory in accordance with EU Directive 2004/23/EC and associated tissue safety regulations.
Warnings and Precautions
Spherox should only be applied by an orthopedic surgeon with specific experience in cartilage surgery and in an accredited surgical environment. Before the biopsy procedure, the joint must be evaluated with high-quality MRI to confirm the location, size and depth of the defect, and to exclude other pathology that would contraindicate treatment. Standing long-leg radiographs are required to assess lower-limb alignment; in patients with varus or valgus malalignment exceeding approximately 5° from the mechanical axis, a corrective osteotomy is typically performed at the time of implantation or in a separate staged procedure to unload the repair site.
Meniscal deficiency increases contact stresses on the cartilage repair and is associated with less favourable outcomes. In patients with significant meniscal loss (particularly in the compartment being treated), meniscal repair, allograft meniscal transplantation, or collagen/polyurethane meniscal scaffolds may be considered concurrently. Similarly, ligamentous instability (especially anterior cruciate ligament [ACL] insufficiency) must be addressed, typically with ligament reconstruction at or before implantation. Patellofemoral alignment problems (patella alta, trochlear dysplasia, elevated tibial tubercle–trochlear groove distance) may require tibial tubercle osteotomy or medial patellofemoral ligament reconstruction for patellar defects.
Body mass index (BMI) is an important consideration. Although there is no absolute cut-off in the European label, clinical outcomes are generally better in patients with a BMI below 30–35 kg/m², and severe obesity is a relative contraindication. Smoking has been associated with impaired cartilage repair and wound healing in the broader orthopedic literature; patients are therefore strongly advised to stop smoking before and during the treatment process.
Between biopsy and implantation — a period of approximately 6 to 8 weeks — the patient will be contacted by the manufacturer and the treatment centre to confirm the scheduled implantation date. If implantation must be postponed, the manufacturer can, within certain limits, cryopreserve the cultured cells. However, delays beyond the validated shelf life may require a new biopsy. The implantation must not proceed if the vial shows any sign of turbidity, visible particulate matter beyond the characteristic spheroids, discoloration, or a broken container.
Patients who do not address concurrent problems — malalignment, instability, meniscal deficiency, infection, or advanced osteoarthritis — have significantly worse outcomes after cartilage cell therapy. A multidisciplinary evaluation including standing long-leg radiographs, high-resolution MRI and, when indicated, diagnostic arthroscopy should be performed before committing the patient to the two-stage Spherox procedure.
Drug Interactions
Because Spherox acts locally in the joint and is not absorbed systemically to any clinically meaningful extent, classical pharmacokinetic drug–drug interactions do not apply. However, several pharmacological categories require specific consideration in the peri-operative period and during the critical early phase of cartilage regeneration (see the dedicated interaction section below for further detail).
Pregnancy and Breastfeeding
There are no clinical data on the use of Spherox in pregnant or breastfeeding women. Because Spherox is an elective surgical treatment for a non-life-threatening condition, and because any knee surgery of this magnitude carries risks that are better avoided during pregnancy (including the need for general or spinal anesthesia and for extended partial weight-bearing rehabilitation), Spherox treatment should be postponed until after pregnancy and breastfeeding are complete. Women of childbearing potential should use effective contraception in the peri-operative period and should discuss timing carefully with the orthopedic surgeon.
Effects on Driving and Use of Machines
Spherox itself has no direct influence on the ability to drive or operate machinery. However, the surgical procedure and the subsequent rehabilitation regimen — typically including a period of restricted weight-bearing (often 6 weeks), use of crutches, bracing, and the prescription of analgesics including, in some cases, opioids — will temporarily impair the ability to drive safely. Patients should not drive until they can comfortably bear full weight without crutches, have regained protective reflexes in the operated leg, and are no longer taking medications that could impair alertness or reaction time. Most patients return to driving an automatic-transmission car after approximately 6–8 weeks and a manual-transmission car after 8–12 weeks, but this should be individualized and confirmed with the treating physician.
Children and Adolescents
Spherox is not indicated in children or adolescents whose epiphyseal growth plates around the knee are still open. Cartilage repair strategies in this population must take into account active skeletal growth, the potential influence on physeal development, and the different biological environment of the juvenile joint. In skeletally immature patients with symptomatic cartilage defects, alternative strategies should be considered and treatment should be planned in a pediatric orthopedic or sports medicine centre.
Older Adults
No specific age-related dose adjustment is required for Spherox within the adult population. However, with increasing age, patients are more likely to have generalized cartilage wear, meniscal degeneration, or early osteoarthritis, which may make them less suitable candidates for a focal cartilage repair strategy. In patients over approximately 50–55 years of age, careful evaluation is needed to determine whether the defect is truly focal or part of a broader degenerative process; joint-preserving alternatives or, in selected cases, partial or total knee arthroplasty may be more appropriate.
How Does Spherox Interact with Other Drugs?
Spherox consists of autologous cells suspended in a physiological medium and is delivered directly into a surgically prepared cartilage defect. There is no hepatic first-pass metabolism, no interaction with cytochrome P450 (CYP) enzymes, and no meaningful systemic plasma concentration. Consequently, traditional pharmacokinetic interactions seen with orally or parenterally administered drugs do not apply. Pharmacodynamic considerations, however, remain important because certain medications can influence the local biological environment in which the implanted chondrocytes need to survive, proliferate, and synthesize new matrix.
Major Interactions and Considerations
Intra-articular corticosteroid injections into the operated knee are generally contraindicated in the weeks before biopsy and for at least 6–12 months after implantation. Corticosteroids are known to suppress chondrocyte metabolism, reduce proteoglycan synthesis, and impair extracellular matrix production, potentially jeopardizing the maturation of the repair tissue. Systemic long-term corticosteroid use poses similar concerns and may also impair wound healing and increase the risk of infection; the benefit of Spherox in such patients should be reconsidered on a case-by-case basis.
Systemic immunosuppressive or immunomodulatory therapy (for example methotrexate, azathioprine, ciclosporin, biologic DMARDs, JAK inhibitors) is a relative concern because it indicates the presence of an underlying inflammatory disease that itself may compromise cartilage repair outcomes. In addition, altered immune function may affect infection risk and local healing. These patients should be discussed in a multidisciplinary team including their rheumatologist before proceeding.
| Drug / Drug Class | Interaction Type | Clinical Recommendation |
|---|---|---|
| Intra-articular corticosteroids (triamcinolone, methylprednisolone) | Local pharmacodynamic – suppress chondrocyte matrix synthesis and may impair repair tissue formation | Avoid for at least 3 months before biopsy and 6–12 months after implantation |
| Systemic corticosteroids (prednisolone, dexamethasone) | Pharmacodynamic – impaired wound healing, increased infection risk, suppressed chondrogenesis | Use the lowest effective dose; consult the prescribing physician before and after implantation |
| Long-term NSAIDs (ibuprofen, naproxen, diclofenac, COX-2 selective agents) | Pharmacodynamic – may impair bone and cartilage healing; also affect subchondral bone remodelling | Limit to short courses for acute pain; prefer paracetamol/acetaminophen where possible during early healing |
| Systemic immunosuppressants (methotrexate, ciclosporin, biologics, JAK inhibitors) | Pharmacodynamic – altered healing and infection risk; underlying inflammatory disease may compromise repair | Multidisciplinary review with rheumatology team; optimize underlying disease control before implantation |
| Anticoagulants (warfarin, DOACs, heparin) | Increased peri-operative bleeding and haemarthrosis risk | Bridge/withhold according to surgical anticoagulation protocols; restart only when haemostasis is assured |
| Antiplatelet agents (aspirin, clopidogrel) | Increased peri-operative bleeding risk | Manage in line with surgical society guidelines; consider temporary withdrawal if cardiovascular risk permits |
| Tobacco and nicotine (not a medication but clinically relevant) | Pharmacodynamic – vasoconstriction, impaired microcirculation, delayed tissue healing | Strongly advise smoking cessation at least 4–8 weeks before biopsy and throughout rehabilitation |
| Vaccines | No known interaction with Spherox itself | Follow standard vaccination schedules; live vaccines generally avoided during active immunosuppression |
| Hyaluronic acid injections | Potential overlap of local action; clinical significance unclear | Avoid intra-articular viscosupplementation in the weeks before biopsy and early post-implantation phase |
Minor or Theoretical Interactions
Bisphosphonates and other bone-active drugs (denosumab, teriparatide) theoretically could influence the subchondral bone plate, which is an important partner of the cartilage repair tissue. However, no clinically significant interaction has been reported in the existing clinical datasets for Spherox. These medications should be reviewed on an individual basis. Similarly, local anesthetics and intra-articular bupivacaine have been shown in laboratory studies to be potentially chondrotoxic at high concentrations; the use of pumps or prolonged intra-articular catheters delivering local anesthetic should be avoided after cartilage cell therapy, in line with broader cartilage-preservation practice.
Overall, the single most important principle is to maintain transparent communication between the orthopedic team, the family doctor, the pharmacy and any specialists (rheumatology, pain medicine, cardiology) who prescribe chronic medications. Bring a complete and up-to-date medication list to every appointment and inform your surgeon before any new prescription or over-the-counter product is started during the treatment and rehabilitation period.
What Is the Correct Dosage of Spherox?
The dosing of Spherox differs fundamentally from conventional medicines. It is not administered at a fixed mg dose, not titrated to clinical response, and not repeated on a schedule. Instead, a sufficient quantity of spheroids is manufactured to cover the specific cartilage defect area measured during the initial arthroscopy. The product is supplied in ready-to-use vials and the total number of spheroids is tailored individually to each patient.
Adults
Implantation Dose
The recommended implantation dose is 10 to 70 spheroids per cm² of cartilage defect. Total defect area treated in the pivotal clinical studies ranged from approximately 1 cm² up to 10 cm². There is no evidence that exceeding 70 spheroids per cm² provides additional clinical benefit, and densities below 10 per cm² may not reliably cover the defect surface.
- Small defects (1–2 cm²): a single vial is usually sufficient to achieve the target density
- Medium defects (2–5 cm²): multiple vials matched to defect size
- Large defects (5–10 cm²): a correspondingly larger batch is manufactured; defects larger than 10 cm² are outside the studied range
Children and Adolescents
Not Indicated Below Skeletal Maturity
Spherox is not indicated in patients whose epiphyseal growth plates are still open. No specific pediatric dose has been established, and the safety and efficacy of Spherox have not been evaluated in children or skeletally immature adolescents. Young patients with symptomatic cartilage defects should be referred to specialist pediatric orthopedic or sports medicine centres, where alternative repair strategies can be considered.
Older Adults
No Age-specific Dose Adjustment
No dose adjustment is required based on age alone within the adult population. However, patient selection becomes more important with advancing age because of the increasing prevalence of generalized osteoarthritis and degenerative meniscal pathology. In patients above approximately 50–55 years, careful assessment is needed to ensure that the defect is truly focal and not part of a broader degenerative process.
Patients with Hepatic or Renal Impairment
No Systemic Exposure – No Dose Adjustment
Because Spherox acts exclusively at the local implantation site and is not eliminated via the liver or kidneys, there is no need for dose modification in patients with hepatic or renal impairment. However, general peri-operative anesthetic and analgesic plans must take organ function into account.
Missed Dose
Spherox is administered as a single procedure rather than a recurring schedule, so the concept of a “missed dose” does not apply in the traditional sense. If the planned implantation is postponed after biopsy — for example because of a post-operative complication, a concurrent infection or an unrelated illness — the manufacturer can store the cultured spheroids for a limited time within the validated shelf life. If this window is exceeded, a new cartilage biopsy and a new manufacturing cycle will be required. Patients should promptly inform the treatment centre of any event that may affect the implantation date.
Overdose
Overdose in the pharmacological sense is not a relevant concept for Spherox. Applying a markedly higher density than 70 spheroids per cm² might theoretically lead to exuberant graft tissue and an increased incidence of cartilage hypertrophy, which is a known post-implantation finding on MRI. Clinically significant local or systemic toxicity from excess spheroid density has not been reported. There is no specific antidote. If cartilage hypertrophy becomes symptomatic (mechanical symptoms, persistent pain), arthroscopic debridement can be considered.
Administration Procedure
The overall Spherox treatment pathway is a structured two-stage process:
| Phase | What Happens | Timing | Notes |
|---|---|---|---|
| Assessment | Clinical examination, MRI, standing long-leg X-rays, planning | Before treatment decision | Multidisciplinary evaluation recommended |
| Biopsy (Stage 1) | Arthroscopic harvesting of healthy cartilage (~200 mg) from a non-weight-bearing area | Day 0 | Short outpatient procedure under general or regional anesthesia |
| Laboratory culture | Chondrocyte isolation, expansion, and self-assembly into spheroids | ~6–8 weeks | GMP-certified manufacturing facility; quality controls performed |
| Implantation (Stage 2) | Defect debridement and implantation of 10–70 spheroids per cm² | Day 42–56 (approx.) | Arthroscopic or mini-arthrotomy; typically 1–2 nights inpatient stay |
| Rehabilitation | Continuous passive motion, graded weight-bearing, physiotherapy | Weeks 0–52 | Return to contact sports usually not before 12–18 months |
| Follow-up | Clinical review and MRI (MOCART scoring) | 6, 12, 24 months and beyond | Long-term monitoring to confirm durable repair |
At the implantation procedure, the surgeon accesses the cartilage defect via arthroscopy or a mini-arthrotomy, removes damaged tissue down to a stable, vertical cartilage rim and to the subchondral bone plate (while avoiding iatrogenic penetration of subchondral bone), thoroughly irrigates the site, and dries the defect. The spheroid suspension is then drawn up and applied directly into the defect with a specialized applicator, ensuring uniform distribution and contact with the surrounding walls. The knee is held still for approximately 10–20 minutes to allow the spheroids to self-adhere, after which range of motion is gently tested and the wound is closed in layers.
Rehabilitation Schedule
Post-operative rehabilitation is a critical determinant of success. A typical programme — individualized according to defect location (femoral condyle vs. patella), defect size, concomitant procedures, and patient factors — includes: continuous passive motion (CPM) started on day 1 to stimulate chondrocyte function and nutrition; bracing in extension for walking initially; partial weight-bearing with crutches for approximately 6 weeks followed by progressive loading; physiotherapy focused on range of motion, quadriceps activation, and gait re-education; low-impact aerobic activity (stationary cycling, swimming) from around week 6–8; running and sport-specific training from 6–9 months at the earliest; and return to pivoting or contact sports generally not before 12–18 months post-implantation, guided by clinical and MRI reassessment. Patellofemoral defects often have slightly different loading protocols compared to femoral condylar defects.
Duration of Effect
Spherox is designed to produce a durable biological repair of the cartilage surface. Clinical trials and registry data have demonstrated sustained improvement in pain and function for at least 5 years, with the longest published follow-up extending beyond 10 years for earlier-generation chondrocyte products of the same class. The treatment is not repeated on a regular schedule. In the uncommon event of graft failure or progression of the defect, a revision procedure may be considered depending on the clinical situation and remaining treatment options.
What Are the Side Effects of Spherox?
Like all therapies, Spherox can cause side effects, although not every patient experiences them. It is important to distinguish two categories: adverse events related to the surgical procedure (anesthesia, arthroscopy, wound healing, temporary immobilization) and events specifically related to the implanted cell product. Most reported side effects belong to the first category and are common to any cartilage or knee surgery. Serious adverse events that can be attributed specifically to the implanted spheroids are uncommon, and the overall safety profile has been considered favourable by the European Medicines Agency across both randomized and post-authorization data.
The frequency categories below follow the MedDRA convention used in the European Summary of Product Characteristics: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10 000 to < 1/1000), very rare (< 1/10 000), and not known (cannot be estimated from available data).
Very Common
May affect more than 1 in 10 people
- Joint effusion (fluid accumulation in the knee)
- Arthralgia (joint pain) at the operated knee
- Cartilage hypertrophy (overgrowth of repair tissue visible on MRI)
- Bone marrow oedema on MRI (usually transient)
Common
May affect up to 1 in 10 people
- Joint swelling and stiffness
- Reduced range of motion of the knee
- Crepitus or mechanical symptoms (clicking, catching)
- Post-operative pain requiring analgesia
- Muscle weakness (quadriceps atrophy during rehabilitation)
- Delayed wound healing
- Intra-articular loose body formation
Uncommon
May affect up to 1 in 100 people
- Haemarthrosis (bleeding into the joint)
- Deep venous thrombosis of the lower limb
- Persistent joint effusion requiring aspiration
- Delamination or partial detachment of the repair tissue
- Subchondral cyst formation
- Allergic reaction to components of the suspension medium
Rare
May affect up to 1 in 1,000 people
- Septic arthritis (intra-articular infection)
- Pulmonary embolism secondary to venous thromboembolism
- Complex regional pain syndrome (CRPS)
- Graft failure requiring revision surgery
- Neurovascular injury related to the surgical approach
Frequency Not Known
Cannot be estimated from available data
- Progression of pre-existing osteoarthritis of the knee
- Long-term safety beyond 10 years in individual patients
Cartilage hypertrophy deserves particular comment because it is one of the most frequently reported imaging findings after autologous chondrocyte therapies. It refers to repair tissue that fills the defect beyond the level of the surrounding native cartilage surface. On serial MRI this appearance is often observed in the first 12 months and, in most cases, remodels over time without symptoms. In a minority of patients, hypertrophy causes persistent mechanical symptoms (catching, pain) and may require arthroscopic debridement. The incidence of clinically significant hypertrophy appears lower with modern, matrix-associated technologies such as Spherox than with first-generation ACI techniques that used periosteal flaps.
Bone marrow oedema in the subchondral bone under the repaired defect is another very common MRI finding. It typically reflects the biomechanical remodelling of the subchondral bone plate in response to the new loading environment and usually diminishes over 12–24 months. Persistence beyond 24 months, especially with ongoing pain, may require additional investigation.
Venous thromboembolism (deep vein thrombosis and pulmonary embolism) is a risk of any knee surgery with prolonged reduced mobility. Mechanical prophylaxis (intermittent pneumatic compression, graduated compression stockings, early mobilization with CPM) and, when appropriate, pharmacological thromboprophylaxis (low-molecular-weight heparin or direct oral anticoagulants) are used according to institutional protocols and patient risk factors.
Septic arthritis is a rare but serious complication of any intra-articular procedure. Strict aseptic technique during biopsy and implantation, peri-operative antibiotic prophylaxis per local guidelines, and vigilance during follow-up minimize this risk. Any acute, severe knee pain with fever, warmth and inability to move the joint after Spherox implantation should be considered an emergency and evaluated urgently.
Contact your orthopedic team or seek emergency care urgently if you experience: sudden severe pain, rapidly increasing swelling, redness or warmth of the knee (possible septic arthritis); calf pain, swelling or redness (possible deep vein thrombosis); sudden shortness of breath, chest pain or coughing up blood (possible pulmonary embolism); signs of systemic allergic reaction including facial swelling, widespread rash, or difficulty breathing; or fever above 38.5 °C with increasing joint symptoms in the weeks following surgery.
Reporting Side Effects
If you experience any side effects, talk to your doctor, surgeon, or pharmacist. This includes any possible side effects not listed in the European package leaflet. In Europe, side effects can also be reported directly to the national pharmacovigilance authority (for example the MHRA Yellow Card Scheme in the UK, ANSM in France, or the BfArM in Germany). Reporting helps to continually improve the safety profile of advanced therapies like Spherox.
How Should You Store Spherox?
Spherox is fundamentally different from conventional pharmaceutical products because it contains living, metabolically active human cells. Consequently, its storage and handling requirements are highly specific and are the exclusive responsibility of the hospital pharmacy and the surgical team. The following information is primarily provided for healthcare professionals, but it is useful for patients and caregivers to understand so that delays or handling problems can be anticipated and avoided.
Spherox is delivered directly from the manufacturing facility to the hospital using a validated transport system that maintains a controlled temperature range, typically 15–25 °C. Unlike many biological medicines, Spherox must not be refrigerated and must not be frozen, as both conditions would compromise the viability and function of the chondrocytes. Exposure to temperatures below 15 °C or above 25 °C outside the validated transport system is not permitted.
Upon arrival at the hospital, the product should be inspected for container integrity, labelling accuracy, and any visible changes (such as turbidity beyond the characteristic appearance of spheroids). If any irregularity is detected, the manufacturer must be contacted immediately before use. The suspension should appear as a clear or slightly opalescent medium with visible rounded spheroids; it must not contain clumps, fibers, strings, discoloured material, or cloudy debris.
Spherox has a very short shelf life once released for implantation — typically measured in hours rather than days. The exact use-by time is printed on the vial and accompanying documentation and must be strictly observed. If the scheduled implantation is delayed beyond this time, the product must not be used. The surgeon should be notified as early as possible of any anticipated delay so that the manufacturer can attempt to reschedule the release of the next batch within the acceptable window.
The product must be used in the operating theatre immediately before implantation. Once the vial is opened and the suspension is drawn into the applicator, it must be applied without further delay. Any unused material from the single-use vial must be discarded according to local regulations for biological waste.
Because Spherox contains live human cells, disposal of unused or leftover material — and of materials that have come into contact with the product — must follow institutional protocols for biological waste and the relevant national regulations on the handling of human tissues and cells. It must not be discarded via ordinary clinical waste streams or household waste.
Patients and caregivers are not expected to store or handle Spherox themselves. However, if you receive any written information or prescription relating to the manufacturing process, keep it in a safe place, and follow the instructions given by the treatment centre regarding the dates of your biopsy, implantation, and pre-operative assessment. Contact the treatment centre promptly if any circumstances (infection, illness, travel) may affect the planned surgical date.
What Does Spherox Contain?
The active substance in Spherox is “spheroids of human autologous matrix-associated chondrocytes.” This long descriptive name reflects the nature of the product. “Spheroids” refers to small, three-dimensional, approximately spherical aggregates — a form of microtissue rather than a simple cell suspension. “Human autologous” means that the cells come from the patient themselves; the product is therefore individually manufactured for each treated patient and cannot be used in any other person. “Matrix-associated” means that the chondrocytes are embedded in their own extracellular matrix, which they have synthesized during laboratory culture; this matrix is rich in type II collagen and proteoglycans and mimics the composition of native hyaline cartilage.
Each spheroid contains approximately 200,000 chondrocytes, and the total number of spheroids delivered is tailored to the measured cartilage defect to achieve the target density of 10–70 spheroids per cm². The spheroids are approximately 500–800 micrometres in diameter, which makes them visible to the naked eye as small, semi-transparent beads within the transport medium.
The remaining components (excipients) of the product are contained in the suspension medium. The suspension medium is a clear, sterile, physiological balanced salt solution designed to maintain chondrocyte viability during transport and implantation. The principal component is sodium chloride at physiological concentration; the medium is buffered to neutral pH and does not contain antibiotics, preservatives, animal serum, or any synthetic carrier (no scaffold, no hydrogel, no fibrin glue). The exact composition of the medium is documented in the product's technical dossier and may vary according to the batch as approved by the regulatory authority.
Because Spherox is an autologous product, the cellular component is fully matched to the recipient immunologically. There is no graft-versus-host risk, no risk of classical immune rejection, and no need for any systemic immunosuppression before, during, or after implantation. The risk of transmission of infectious agents from donor to recipient is also eliminated, since the donor and the recipient are the same person. The starting cartilage biopsy is nevertheless tested in accordance with European tissue safety regulations for the presence of specific infectious markers (HIV, hepatitis B and C, syphilis) to protect the laboratory personnel and the integrity of the manufacturing process.
The finished product is supplied in a sterile single-use vial, labelled with the patient's identification, the batch number, the date of release, and the strict use-by time. The suspension should be clear to slightly opalescent, with visible spheroids in suspension or loosely settled at the bottom of the vial. Before implantation, the surgical team confirms the match between patient identity and product label, inspects the vial, and follows the manufacturer's instructions for resuspension and application. Nothing else is added to the product, and it is not mixed with any other medication.
Appearance of packaging: the product is delivered in a validated, temperature-controlled shipping container, together with documentation required for traceability under EU ATMP and tissue safety legislation. Chain of custody is maintained from cartilage biopsy through culture, quality release, shipping, and final implantation, in line with full traceability requirements for advanced therapy medicinal products.
Frequently Asked Questions About Spherox
Spherox is an advanced therapy medicinal product (ATMP) used to biologically repair symptomatic cartilage defects of the femoral condyle and patella of the knee in adult patients. It is indicated specifically for focal cartilage lesions classified as ICRS grade III or IV, with a defect area of up to 10 cm². It is not a treatment for generalized osteoarthritis, rheumatoid arthritis, or cartilage defects in children and adolescents whose growth plates are still open.
Spherox is an autologous cell therapy, meaning the cells come from the patient. During an initial arthroscopy, a small sample of healthy cartilage (about 200 mg) is taken from a non-weight-bearing part of the knee. In a specialized GMP laboratory, chondrocytes are isolated and cultured for 6–8 weeks, during which they self-organize into three-dimensional spheroids embedded in their own extracellular matrix. At a second surgical procedure, the defect is debrided and the spheroid suspension is applied directly into the defect at a density of 10–70 spheroids per cm². The spheroids self-adhere within about 20 minutes, without the need for glue, membrane or sutures.
Cartilage regeneration is a slow biological process. Patients typically report a gradual improvement in pain and function over the first 6 to 12 months, with continued maturation of the repair tissue on MRI over 12–24 months. Clinical benefits have been shown to persist for at least 5 years in randomized controlled trials. Structured rehabilitation — including continuous passive motion, progressive weight-bearing, and physiotherapy — is essential to achieve and maintain a good outcome, and the rehabilitation programme usually extends over 9–12 months.
Most side effects relate to the knee surgery rather than to the implanted cells themselves. Very common findings include joint effusion, joint pain, cartilage hypertrophy (visible on MRI), and bone marrow oedema, most of which are transient and resolve with rehabilitation. Common post-operative issues include stiffness, reduced range of motion, and temporary quadriceps weakness. Uncommon or rare complications include deep venous thrombosis, graft delamination, septic arthritis, and complex regional pain syndrome. The overall safety profile has been assessed as favourable by the European Medicines Agency.
There are no clinical data on the use of Spherox in pregnant or breastfeeding women. Because Spherox is an elective treatment for a non-life-threatening condition and because any major surgery should generally be avoided during pregnancy, Spherox treatment should be postponed until after pregnancy and breastfeeding. Women of childbearing potential should use effective contraception during the peri-operative period and discuss the timing of treatment carefully with their surgeon.
Microfracture is a single-stage, lower-cost bone-marrow stimulation technique suitable for small defects (typically <2 cm²). Its repair tissue tends to be fibrocartilage, with durability that may decline over time. Spherox and other matrix-associated autologous chondrocyte implantation (MACI) products are two-stage cell therapies designed to produce hyaline-like cartilage and are typically preferred for larger defects or after a failed primary marrow-stimulation procedure. Head-to-head randomized data (CS-ATMP-03) demonstrate that Spherox is non-inferior to microfracture over 2 years, with a tendency toward more durable outcomes at 5 years, particularly in defects larger than 2 cm². The most appropriate technique depends on defect characteristics, patient goals, and local expertise.
Return-to-activity timelines depend on the defect location, size, concomitant procedures, physical demands of the job or sport, and rehabilitation progress. Sedentary office work is often possible from 1–3 weeks after implantation, once wound healing and pain control allow. Light manual work typically returns between 6 and 12 weeks. Low-impact activities such as stationary cycling and swimming usually start around 6–8 weeks, running from 6–9 months at the earliest, and pivoting or contact sports generally not before 12–18 months. Your surgeon and physiotherapist will personalize this plan based on clinical progress and, when appropriate, MRI findings.
References
- European Medicines Agency (EMA). Spherox (spheroids of human autologous matrix-associated chondrocytes) – Summary of Product Characteristics and European Public Assessment Report. Available at: EMA – Spherox EPAR
- Niemeyer P, Albrecht D, Andereya S, et al. Autologous chondrocyte implantation (ACI) for cartilage defects of the knee: A guideline by the working group “Clinical Tissue Regeneration” of the German Society of Orthopaedics and Trauma (DGOU). Knee. 2016;23(3):426–435. doi:10.1016/j.knee.2016.02.001
- Niemeyer P, Laute V, Zinser W, et al. A Prospective, Randomized, Open-Label, Multicenter, Phase III Noninferiority Trial to Compare the Clinical Efficacy of Matrix-Associated Autologous Chondrocyte Implantation With Spheroid Technology Versus Microfracture in Patients With Cartilage Defects of the Knee. Orthopaedic Journal of Sports Medicine. 2019;7(7):2325967119854442. doi:10.1177/2325967119854442
- Niemeyer P, Laute V, John T, et al. Efficacy of Autologous Chondrocyte Implantation With Spheroid Technology Is Independent of Spheroid Dose After 4 Years. American Journal of Sports Medicine. 2020;48(6):1473–1481. doi:10.1177/0363546520914365
- Brittberg M, Recker D, Ilgenfritz J, et al. Matrix-Applied Characterized Autologous Cultured Chondrocytes Versus Microfracture: Five-Year Follow-up of a Prospective Randomized Trial. American Journal of Sports Medicine. 2018;46(6):1343–1351. doi:10.1177/0363546518756976
- Kon E, Filardo G, Brittberg M, et al. A multilayer biomaterial for osteochondral regeneration shows superiority vs microfractures for the treatment of osteochondral lesions in a multicentre randomized trial at 2 years. Knee Surgery, Sports Traumatology, Arthroscopy. 2018;26(9):2704–2714.
- Mithoefer K, Saris DBF, Farr J, et al. Guidelines for the Design and Conduct of Clinical Studies in Knee Articular Cartilage Repair: International Cartilage Repair Society (ICRS) Recommendations. Cartilage. 2011;2(2):100–121.
- Angele P, Fritz J, Albrecht D, et al. Defect type, localization and matrix fixation determine outcome of matrix-associated autologous chondrocyte implantation. Archives of Orthopaedic and Trauma Surgery. 2015;135(12):1707–1715.
- Committee for Advanced Therapies (CAT). Reflection paper on classification of advanced therapy medicinal products. European Medicines Agency; latest revision 2024.
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