Marc Darrow, MD, JD

Regenerative medicine is one of the most discussed—and frequently misunderstood—areas of musculoskeletal care. Patients often hear terms such as stem cells, platelet-rich plasma, bone marrow concentrate, and tissue regeneration used as if they mean the same thing. They do not.

This article provides a practical introduction to regenerative medicine and explains what mesenchymal stem cells are, why many scientists now call them mesenchymal stromal cells, how cell-based procedures differ from one another, and what the current evidence can and cannot tell us.

The goal is not to promise that an injection can “regrow” an arthritic joint. It is to help patients understand the biology, the terminology, the limits of the research, and the questions they should ask before considering treatment.

What is regenerative medicine?

Regenerative medicine is a broad field that studies ways to support the repair, replacement, or restoration of damaged cells, tissues, and organs. It includes basic laboratory research, tissue engineering, gene therapy, cell-based therapies, and biologic treatments that use substances obtained from a patient’s own body.

In orthopedic and sports medicine practice, the term is most often used for treatments intended to influence the local healing environment. These may include:

  • Platelet-rich plasma (PRP), prepared from a patient’s blood
  • Bone marrow aspirate concentrate (BMAC or BMC), prepared from bone marrow
  • Certain adipose-derived preparations, subject to important regulatory distinctions
  • Prolotherapy, which uses an irritant solution to stimulate a localized healing response
  • Tissue-engineering products and culture-expanded cell therapies, most of which remain investigational for routine orthopedic use

These treatments are not identical. They contain different cells, proteins, growth factors, signaling molecules, and concentrations. Their preparation methods also vary. Therefore, evidence for one product or procedure should not automatically be applied to another.

What is a stem cell?

A true stem cell has two defining biological abilities:

  1. Self-renewal: It can divide and produce additional cells with stem-cell properties.
  2. Differentiation: Under appropriate conditions, it can develop into one or more specialized cell types.

Stem cells are commonly classified by the range of cells they may produce. Pluripotent stem cells can potentially form nearly every cell type in the body. Adult tissue-specific stem and progenitor cells have more limited potential and help maintain or repair particular tissues.

The cells discussed in musculoskeletal regenerative medicine are adult cells, not embryonic stem cells.

What are mesenchymal stem cells?

The term mesenchymal stem cell, abbreviated MSC, has traditionally described a population of adult cells that can be isolated from tissues such as bone marrow and grown in a laboratory. Under controlled laboratory conditions, some of these cells can form bone-, cartilage-, and fat-like cells. This multilineage potential helped establish the original “stem cell” description. (1)

In 2006, the International Society for Cellular Therapy proposed minimum laboratory criteria for identifying culture-expanded MSCs. The cells must adhere to plastic under standard culture conditions, display a particular set of surface markers, and demonstrate the ability to differentiate into bone, cartilage, and fat lineages in laboratory testing. (2)

This definition is useful in research, but it does not mean that every injection advertised as a “stem cell treatment” contains a uniform population of proven stem cells. A mixed, minimally processed tissue preparation used during a same-day procedure is biologically different from a purified and culture-expanded cell product studied in a laboratory.

Why are they also called mesenchymal stromal cells?

Many researchers now prefer the term mesenchymal stromal cells. The abbreviation remains MSC, which can create confusion.

“Stromal” refers to supportive cells within tissue. The newer terminology recognizes that many cells classified as MSCs may influence repair through signaling and immune-modulating activity rather than by permanently transforming into new cartilage, tendon, or bone. The International Society for Cell & Gene Therapy has emphasized the need to identify the tissue source and provide evidence for the specific properties being claimed. (3)

Some investigators have also proposed the name medicinal signaling cells to highlight the possibility that MSCs act mainly by releasing biologically active signals that influence nearby cells. (4)

For patients, the key point is simple: the word stem cell can suggest that injected cells directly rebuild an entirely new joint surface. That is not an established description of what happens after most orthopedic cell-based procedures.

Where do mesenchymal stromal cells come from?

MSC-like cells have been studied in bone marrow, adipose tissue, umbilical cord tissue, dental pulp, synovium, and other connective tissues. However, cells obtained from different tissues are not automatically equivalent. Their characteristics may vary according to the donor, tissue source, collection technique, processing method, laboratory conditions, cell dose, and intended use.

Bone marrow

Bone marrow is one of the best-studied sources in orthopedic medicine. In a same-day autologous procedure, autologous means that the material comes from and is returned to the same patient.

Bone marrow may be aspirated—commonly from the back of the pelvic bone—and processed to reduce red blood cells and concentrate a mixed nucleated-cell fraction. The resulting bone marrow aspirate concentrate contains platelets, white blood cells, signaling proteins, hematopoietic cells, and a relatively small number of cells capable of forming connective-tissue colonies in culture.

Bone marrow concentrate should not be described as a syringe filled only with stem cells. It is a heterogeneous biologic preparation, and its composition varies from patient to patient and from one processing system to another.

Adipose tissue

Fat tissue also contains stromal and vascular cells. The method used to obtain and process adipose tissue matters greatly. Minimally processed fat, enzymatically isolated stromal vascular fraction, and culture-expanded adipose-derived stromal cells are different products and may fall under different regulatory requirements.

Birth-tissue products

Products marketed as coming from umbilical cord, Wharton’s jelly, amniotic tissue, or placental tissue require particular caution. Patients should not assume that a vial contains living stem cells merely because the product name includes words such as birth tissue, cord, or regenerative. The exact contents, viability, sterility testing, donor screening, regulatory status, and clinical evidence should be verified.

How might MSCs influence injured or arthritic tissue?

Several mechanisms are being investigated.

Cell signaling

MSCs can release cytokines, growth factors, extracellular vesicles, and other signals in laboratory and preclinical studies. These signals may affect inflammation, blood-vessel formation, cell survival, and the activity of local repair cells. This is sometimes called a paracrine effect, meaning that a cell influences nearby cells through released signals.

Immune modulation

MSCs have shown the ability to interact with immune cells and modify inflammatory activity under certain experimental conditions. This does not mean they simply “turn off inflammation.” Inflammation is complex, and the behavior of cells depends on their environment.

Support of tissue repair

MSC-like cells can form bone-, cartilage-, and fat-like tissue in controlled laboratory experiments. Whether, and to what degree, cells delivered during a clinical orthopedic procedure survive, engraft, and become durable new human tissue remains an active area of research.

These proposed mechanisms are scientifically plausible, but a plausible mechanism is not the same as proof of clinical benefit. Patient outcomes must be established through well-designed clinical studies.

What is the difference between bone marrow concentrate and laboratory-expanded MSCs?

This is one of the most important distinctions in regenerative medicine.

Bone marrow aspirate concentrate is generally produced during a same-day procedure by concentrating a patient’s bone marrow. It contains many cell types and biologic components. MSC-like progenitor cells represent only a small part of the final preparation.

Culture-expanded MSCs are isolated and multiplied over days or weeks in a laboratory to produce a much larger cell population. Expansion changes the nature of the product and introduces manufacturing, sterility, quality-control, and regulatory considerations. In the United States, expanded cell products generally require formal regulatory authorization and are not the same as a same-day autologous bone marrow concentrate procedure. Research involving one preparation cannot be used automatically to prove the effectiveness of the other.

What does the orthopedic research show?

Cell-based orthopedic research is growing, particularly for knee osteoarthritis. Some clinical studies report improvements in pain and function after bone marrow- or adipose-derived procedures. However, studies differ considerably in patient selection, processing methods, cell characterization, doses, comparison treatments, rehabilitation protocols, and follow-up periods.

The use of an active comparison or placebo is especially important because symptoms may improve through rehabilitation, natural fluctuation, contextual effects, and other components of care. In one randomized, placebo-controlled study involving bilateral knee osteoarthritis, patients received bone marrow concentrate in one knee and saline in the other. Pain improved in both knees, but the study did not find a significant difference in pain relief between the treated and saline-injected knees at six months. (5)

Other trials have reported favorable outcomes with particular cell preparations, illustrating why the literature cannot be reduced to “stem cells work” or “stem cells do not work.” For example, a randomized study of autologous adipose-derived MSC therapy for knee osteoarthritis reported improvements in pain and function, but the product, cell processing, and protocol were specific to that trial. (6)

At present, it is more accurate to say that some cell-based treatments show potential for selected orthopedic conditions, while uncertainty remains about the best candidates, ideal preparation, dose, durability, structural effects, and comparative effectiveness. Evidence of symptom improvement should not be presented as proof that lost cartilage has been completely regenerated.

Are mesenchymal stem cell treatments FDA approved?

Patients should understand the difference between scientific investigation, medical practice, and FDA approval. The FDA states that regenerative medicine products, including stem cell products, generally require approval before marketing and that these products have not been approved for orthopedic conditions such as osteoarthritis, tendonitis, disc disease, back pain, neck pain, or shoulder pain.

Clinical studies can be registered without proving that a treatment is safe or effective. Likewise, the use of a patient’s own cells does not automatically make every processing method or clinical application FDA approved.

Potential risks and limitations

Risks depend on the tissue source, collection method, processing, injection site, patient health, and whether the product is autologous or donor-derived. Potential risks can include pain, bleeding, infection, temporary swelling, nerve or tissue injury, an adverse reaction, failure to improve, and delay of another treatment that may be more appropriate.

Additional concerns apply to products that are extensively manipulated, culture-expanded, contaminated, improperly stored, or marketed without adequate testing. A patient’s medical history, medications, infection risk, cancer history, blood disorders, and ability to participate in rehabilitation may affect candidacy.

Summary

Mesenchymal stem cells—or, more precisely in many settings, mesenchymal stromal cells—are an important subject of modern regenerative-medicine research. They may influence tissue through signaling, immune modulation, and interactions with the local repair environment. Their biology is more complex than the popular idea that injected cells simply become new cartilage.

Bone marrow concentrate, adipose-derived preparations, donor products, and culture-expanded MSCs are not interchangeable. Patients deserve to know exactly what is being proposed and how closely the supporting evidence matches that specific product, condition, and procedure.

Regenerative medicine may offer a nonsurgical option for selected patients, but it should be approached with accurate diagnosis, careful patient selection, precise technique, realistic expectations, rehabilitation, and honest discussion of uncertainty.

Frequently asked questions

Are mesenchymal stem cells embryonic stem cells?

No. MSCs used or studied in orthopedic medicine are adult tissue-derived cells. They are not embryonic stem cells.

Does bone marrow concentrate contain stem cells?

Bone marrow concentrate contains a mixed population of cells and signaling components. It may contain a small number of cells with mesenchymal progenitor characteristics, but it is not a purified preparation consisting entirely of stem cells.

Can stem cell injections regrow cartilage?

Laboratory and imaging findings in some studies are encouraging, but complete and predictable regrowth of normal joint cartilage has not been established for routine orthopedic injections. Improvement in pain or function does not by itself prove cartilage regeneration.

Are PRP and stem cell procedures the same?

No. PRP is prepared from blood and concentrates platelets and their associated signaling proteins. Bone marrow concentrate is obtained from marrow and contains a different mixture of cells and biologic components.

Who may be a candidate?

Candidacy depends on the diagnosis, severity and location of tissue damage, overall health, prior care, functional goals, and available alternatives. A medical evaluation is necessary; no injection is appropriate for every patient or every joint problem.

References

  1. Pittenger MF, Mackay AM, Beck SC, et al. Multilineage potential of adult human mesenchymal stem cells. Science. 1999;284(5411):143-147. doi:10.1126/science.284.5411.143.
  2. Dominici M, Le Blanc K, Mueller I, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8(4):315-317. doi:10.1080/14653240600855905.
  3. Viswanathan S, Shi Y, Galipeau J, et al. Mesenchymal stem versus stromal cells: International Society for Cell & Gene Therapy Mesenchymal Stromal Cell committee position statement on nomenclature. Cytotherapy. 2019;21(10):1019-1024. doi:10.1016/j.jcyt.2019.08.002.
  4. Caplan AI. Mesenchymal stem cells: Time to change the name!. Stem Cells Translational Medicine. 2017;6(6):1445-1451. doi:10.1002/sctm.17-0051.
  5. Shapiro SA, Kazmerchak SE, Heckman MG, Zubair AC, O’Connor MI. A prospective, single-blind, placebo-controlled trial of bone marrow aspirate concentrate for knee osteoarthritis. American Journal of Sports Medicine. 2017;45(1):82-90. doi:10.1177/0363546516662455.
  6. Freitag J, Bates D, Wickham J, et al. Adipose-derived mesenchymal stem cell therapy in the treatment of knee osteoarthritis: A randomized controlled trial. Regenerative Medicine. 2019;14(3):213-230. doi:10.2217/rme-2018-0160.

Medical disclaimer

This article is for educational purposes and is not medical advice. It does not establish a physician-patient relationship. Stem cell and PRP procedures are not FDA approved for orthopedic conditions. Results vary, and no outcome can be guaranteed. Patients should consult a qualified medical professional about diagnosis, treatment alternatives, risks, regulatory status, and whether a procedure is appropriate for their individual circumstances.