OrthoBiologic Therapies of the Knee

Courtesy: Prof Deiary Kader, London, UK

Focus of lecture:

• • Hyaluronic acid (viscosupplementation)
  • Platelet-rich plasma (PRP)
  • Cell-based therapy (stem cells / mesenchymal cells)

Concept of Biological Regeneration

Natural Regeneration

• Human body possesses innate regenerative capacity.
• Example:
  • Approximately 3 million red blood cells replaced every second.
• Stem or progenitor cells may contribute to:
  • Tissue repair
  • Regeneration of tendons and soft tissues.

Example:

• Studies show hamstring tendon regeneration in ~70% of patients after harvest for ACL reconstruction.

Commercialization of Orthobiologics

Growth of the Industry

• Increasing commercial promotion of:
  • PRP
  • Stem cell therapy
  • Biologic injections

Claims include treatment of:

• Hair loss
• Diabetes
• Neurological diseases
• Arthritis
• Sports injuries

Concerns:

• Lack of regulation
• Limited scientific evidence
• High cost to patients.

Hyaluronic Acid (Viscosupplementation)

Background

• Hyaluronic acid injections commonly used for knee osteoarthritis.
• Numerous commercial preparations exist.

Key Principle

• Hyaluronic acid products are not identical.
• Differences include:
  • Molecular weight
  • Preparation technique
  • Injection protocol.

Evidence from Literature

Cochrane Review (2006)

• Demonstrated some effectiveness.
• However, effect size was small, limiting strong recommendations.

Meta-analysis (54 RCTs)

• Benefit seen:
  • Onset: ~4 weeks
  • Peak: ~8 weeks.

Additional Meta-analyses

Findings vary:

Some show:

• Minimal clinical benefit.

Others report:

• Moderate improvement in symptoms.

Guideline Recommendations

• National Institute for Health and Care Excellence (NICE)
  ? Does not recommend routine use.
• Osteoarthritis Research Society International
  ? Does not strongly support use.
• American Academy of Orthopaedic Surgeons
  ? Previously recommended against routine use.

Clinical Takeaway

• Hyaluronic acid may provide short-term symptom relief.
• Most useful in:
  • Early osteoarthritis

Typical duration of effect:

• 2–3 months

Effect decreases with:

• Advanced joint degeneration.

Platelet-Rich Plasma (PRP)

Composition

PRP contains:

• Platelets
• Growth factors
• Cytokines
• Clotting factors
• Prostaglandins
• Electrolytes (e.g., calcium, potassium)

More than 1100 proteins have been identified.

Types of PRP

PRP preparations vary widely:

• Leukocyte-rich PRP
• Leukocyte-poor PRP
• Different centrifugation protocols:
  • Soft spin
  • Hard spin

Leukocyte-rich PRP:

• Produces stronger inflammatory response.

Evidence in Knee Osteoarthritis

Systematic Reviews

Some studies show:

• Small clinical benefit

Other RCTs report:

• PRP superior to hyaluronic acid.

However, some meta-analyses demonstrate:

• No significant benefit.

PRP in Tendinopathy

Patellar Tendinopathy

Studies comparing PRP with:

• Dry needling
• Shockwave therapy
• Physiotherapy

Result:

• Well-conducted studies generally show no clear benefit.

Limitations of PRP Research

Major problem:

• Lack of standardization

Currently:

• More than 40 commercial PRP preparation systems exist.

Variability occurs in:

• Platelet concentration
• Growth factor content
• Leukocyte count
• Preparation protocol.

Even factors such as:

• Time of day
• Patient characteristics

can affect PRP composition.

Stem Cell and Cell-Based Therapies

Definition of Stem Cells

According to the National Institutes of Health:

Stem cells are cells that:

• Can self-renew
• Are undifferentiated
• Can differentiate into specialized cells.

Types of Stem Cells

Embryonic Stem Cells

• Pluripotent
• Can differentiate into any tissue type.

Adult (Somatic) Stem Cells

• Multipotent
• Found in various tissues.

Induced Pluripotent Stem Cells

• Adult cells genetically reprogrammed to become pluripotent.

Discovery awarded the Nobel Prize in Physiology or Medicine.

Mesenchymal Stem Cells (MSC)

Originally described by Arnold Caplan.

However:

• Later recognized that these are not true stem cells.

Caplan proposed a new name:

• Medicinal signaling cells

Reason:

• Their main role appears to be cell signaling, not direct regeneration.

Mechanism of Action of MSCs

MSCs may act by:

Paracrine Effects

• Secretion of cytokines
• Release of growth factors.

Immunomodulation

• Regulation of immune response.

Trophic Effects

• Promotion of local tissue repair.

Anti-inflammatory Effects

• Reduction of joint inflammation.

Source of MSCs

Common sources:

• Bone marrow
• Adipose tissue
• Perivascular cells (pericytes)

Pericytes:

• Located around blood vessels.
• Activated during injury.

Stem Cells in Knee Conditions

ACL Injuries

• High-quality studies show no significant benefit.

Meniscal Injuries

Some case series suggest:

• Increase in meniscal volume on MRI.

However:

• Measurement reliability is questionable.

Tendinopathy

Small studies show:

• Possible benefit.

Evidence remains low quality.

Knee Osteoarthritis

Evidence includes:

• Case series showing cartilage improvement.
• Randomized trials showing no difference compared to saline injection.

Overall conclusion:

• Evidence remains insufficient.

Limitations of Stem Cell Therapy

Major issues include:

• Lack of standardized protocols
• Unknown composition of injections
• Uncertain mechanism of action
• Poor quality clinical trials
• High risk of bias.

Placebo Effect

Important consideration in orthopaedics.

Studies show:

• Up to 50% of treatment effect may be placebo.

This applies to:

• Injections
• Some surgical interventions.

Future Directions

Potential future therapies include:

Exosomes

• Small extracellular vesicles released by cells.

Characteristics:

• Size: 30–100 nm
• Carry signaling molecules.

Potential uses:

• Targeted regenerative therapy
• Cell-to-cell signaling.

Exosomes may allow:

• Delivery of regenerative factors directly to tissues.

Key Conclusions

• Orthobiologic therapy has significant potential but limited evidence.
• Hyaluronic acid may help early osteoarthritis for short duration.
• PRP evidence is mixed and inconsistent.
• Mesenchymal cells are not true stem cells.
• Current studies lack:
  • Standardization
  • High-quality methodology.

Overall message:

Too much hope, but currently limited scientific evidence