Under standardized conditions, the overall safety of intra-articular MSC injection is good, and serious adverse events are relatively uncommon.

The more common reactions are mild transient reactions such as knee pain, swelling, stiffness, or fever. Most resolve on their own or recover after simple management.

Active infection, active malignancy, and confirmed allergy to product components are clear contraindications. Patients with rheumatoid arthritis, end-stage knee osteoarthritis, previous malignancy, or severe lower-limb alignment abnormalities require more cautious evaluation.

A considerable amount of clinical data has observed the safety of MSC therapy. A meta-analysis spanning 15 years included 62 randomized controlled trials and 546 patients treated with MSCs, covering about 20 diseases. These included 6 trials related to knee osteoarthritis. Overall, the safety of MSC therapy was good.

In patients with knee osteoarthritis, the reported incidence of adverse reactions is about 10% to 30%, and the vast majority are mild, transient local reactions.

Another systematic dataset including 12 randomized controlled trials also found that most adverse reactions were mild, with no clear increase in the risk of serious infection, tumor, or death.

In clinical data, common adverse reactions are mainly concentrated in the short period after injection, such as:

Most of these reactions are mild.

Some patients usually improve within about 1 week after ice application, compression bandaging, and symptomatic management under medical guidance.

These transient reactions may be related to local immune response, inflammation and immune regulation after cell activation, and residual components in the product.

If pain and swelling become progressively worse after injection, with persistent high fever, obvious joint redness and swelling, or inability to move, medical attention is needed promptly to rule out infection and other problems.

In current standardized clinical data, serious infection is uncommon. However, intra-articular injection is an invasive procedure, and any treatment entering the joint cavity requires strict aseptic technique.

More importantly, MSCs are cell products, and their production, culture, transport, storage, and use require high-quality control.

If the cell preparation process is not standardized, the production environment does not meet the corresponding quality management requirements, or the cell product itself lacks strict testing, the risks of infection and immune-related adverse reactions may increase.

Many current MSC clinical trials for knee osteoarthritis exclude patients with a history of malignancy within the past 5 years, so long-term safety data for this group remain limited.

If the patient has been tumor-free for a long time and has a low recurrence risk, the possibility of treatment can be discussed further after evaluation by an oncology specialist.

Knee osteoarthritis is mainly a degenerative joint disease, while rheumatoid arthritis is a chronic immune-mediated inflammatory disease.

Most current MSC clinical trials for knee osteoarthritis have excluded patients with rheumatoid arthritis and other inflammatory arthritides, so sufficient clinical data are lacking for this group.

If rheumatoid arthritis is still active, priority should be given to controlling the systemic immune-inflammatory state.

For patients whose disease is already stable and who also have knee osteoarthritis, rheumatology, sports medicine, or joint surgery specialists can jointly evaluate the case before discussing whether further treatment is appropriate.

The progression of knee osteoarthritis is influenced by inflammation and is also related to mechanical load. For example, in obvious knee varus, the medial side of the knee may bear excessive pressure for a long time.

Even if MSCs improve the local inflammatory environment to some extent, this persistent abnormal loading may continue to drive cartilage wear.

Therefore, patients with severe lower-limb alignment abnormalities first need a doctor to determine the role of mechanical structural problems in the disease.

If patient-derived MSCs are used, the proliferation and differentiation ability of cells in older patients may decline, and cell preparation quality may also be affected by age, metabolic disease, and chronic inflammatory status.

Older patients are also more likely to have cardiovascular disease, diabetes, cancer history, and advanced structural degeneration of the knee at the same time.

MSCs can currently mainly come from tissues such as bone marrow, fat, umbilical cord, and umbilical cord blood.

Cells from different sources differ in expansion capacity, immunomodulatory ability, and preparation processes, but it is not yet possible to confirm that any one source has an absolute advantage in overall safety and efficacy.

Umbilical cord-derived MSCs have relatively strong expansion capacity, relatively standardized donor acquisition, and good industrial accessibility. Bone marrow-derived MSCs have accumulated more clinical data, and fat-derived cells are relatively convenient to obtain.