What are orthobiologics, including types such as platelet-rich plasma (PRP), bone marrow aspirate concentrate (BMAC), and adipose-derived stem cells, and how are they used in current working practices to treat orthopedic conditions?

Overview of Orthobiologics

Orthobiologics are organic and synthetic materials used to augment bone and soft tissue healing in musculoskeletal conditions, but current evidence shows that clinical use has vastly outpaced scientific validation, with major professional organizations strongly recommending against routine use of most orthobiologic therapies due to lack of standardization, insufficient evidence, and concerns about unsubstantiated marketing claims. 1, 2

Definition and Scope

Orthobiologics encompass biological materials derived from autologous tissues or synthetic sources that aim to modulate inflammation, promote tissue repair, and restore homeostasis in musculoskeletal pathologies. 3, 4 The economic burden driving their use is substantial, with musculoskeletal diseases costing approximately $1 trillion annually in the United States (7.4% of GDP), creating patient vulnerability to unproven treatments. 1

Major Types of Orthobiologics

Platelet-Rich Plasma (PRP)

PRP is prepared by centrifuging anticoagulated whole blood to concentrate platelets above the white blood cell layer, followed by a second spin for further concentration. 1 The preparation contains growth factors and cytokines theoretically capable of promoting tissue healing. 3, 5

Current clinical practice reality:

• The American College of Rheumatology/Arthritis Foundation strongly recommends AGAINST PRP for knee and hip osteoarthritis. 2
• The AAOS acknowledges some evidence for pain reduction in knee OA but notes inconsistent results, particularly in severe disease. 2
• Critical limitation: Massive variability exists in platelet concentration, leukocyte presence, activation methods, injection volumes, and treatment frequency—making it impossible to know what is actually being injected. 2, 1

Cell-Based Therapies (Bone Marrow Aspirate Concentrate, Adipose-Derived Cells)

These involve minimally manipulated autologous cell preparations harvested from bone marrow or adipose tissue. 1, 3 The concentration of actual stem or progenitor cells is extremely low—only 1 in 1,000 to 1 in 1,000 cells harvested are true stem/progenitor cells capable of differentiation. 1

Terminology clarification mandated by consensus:

• These preparations should be called "cell therapy," NOT "stem cell therapy," as they are uncharacterized mixed cell populations. 1
• True mesenchymal stem cells (MSCs) are culture-expanded, purified cells meeting specific ISCT criteria (plastic-adherent, express CD73/CD90/CD105, differentiate into osteoblasts/adipocytes/chondrocytes in vitro). 1
• No MSC therapies have FDA approval for musculoskeletal diseases. 6

Current clinical practice reality:

• The ACR/AF strongly oppose routine stem cell injections for knee osteoarthritis. 6
• The AAOS emphasizes no FDA approval exists for MSC treatment of OA. 6
• Safety concerns include thrombosis risk if single injection exceeds 4×10^6 cells/kg body weight, and increased adverse events with frozen-thawed cells. 6

Bone Morphogenetic Protein-2 (BMP-2)

BMP-2 is a growth factor used primarily in spinal fusion and fracture healing applications. 3, 7 This represents one of the more established orthobiologics with specific surgical indications.

Bone Void Fillers and Extracellular Matrix Products

These synthetic and organic materials provide scaffolding for bone regeneration and soft tissue repair. 3, 7 They are used in trauma, spine surgery, and reconstructive procedures to fill defects and support healing.

Current Working Practices: The Evidence-Practice Gap

The Fundamental Problem

Clinical use of orthobiologics has "greatly outpaced the evidence," driven by patient demand, direct-to-consumer marketing, and lack of effective conventional treatments for conditions like osteoarthritis. 1 This has created serious concerns about erosion of public trust and responsible investment in legitimate biological therapies. 1

Recommended Clinical Approach for Osteoarthritis (Primary Use Case)

First-line treatments (use these first):

• Physical therapy and structured exercise programs 2
• Weight management for overweight patients 2
• Oral NSAIDs or topical NSAIDs 2

Second-line intervention:

• Intra-articular corticosteroid injections (benefits last approximately 3 months) 2

NOT recommended routinely:

• PRP therapy (strong recommendation against for hip OA; limited/inconsistent evidence for knee OA) 2, 8
• Hyaluronic acid (moderate to strong recommendations against) 2
• Cell-based therapies (strong recommendation against routine use) 6

When Orthobiologics Are Currently Used Despite Recommendations

In real-world practice, orthobiologics are being offered for:

• Knee osteoarthritis (mild-to-moderate stages show better response than severe disease) 2
• Tendinopathies 9
• Ligament injuries 9
• Articular cartilage defects 9
• Bone defects and fracture nonunions 9

However, this widespread use occurs despite insufficient evidence and against guideline recommendations. 1, 2

Critical Standardization Requirements

If orthobiologics are to be used, the AAOS/NIH consensus mandates minimum reporting standards (MIBO checklist): 1

For PRP preparations, document:

• Exact preparation method enabling replication 1
• Platelet concentration and leukocyte content 1
• Activation method used 1
• Volume and number of injections 1

For cell therapies, document:

• Tissue source and harvest technique 1
• Processing method with specific reagents and timing 1
• Cellular composition and heterogeneity 1
• Immunophenotype and viability percentage 1
• Passage number for cultured cells 1
• Delivery method and volume 1

Institutional Responsibilities

Physicians and institutions offering orthobiologic therapies must establish:

• High-quality patient registries for postmarket surveillance 1
• Biorepository-linked registries for quality assessment 1
• Standardized outcome measurement using validated tools (KOOS pain subscale, PROMIS physical function) 1

This is not optional—it is a consensus recommendation to address the current evidence deficit. 1

Common Pitfalls to Avoid

Marketing versus reality:

• Uncharacterized minimally manipulated cell preparations are being misrepresented as "stem cell therapy" 1
• Direct-to-consumer advertising exploits patients with chronic pain and limited conventional options 1
• The untested and uncharacterized nature of these treatments must be clearly communicated to patients. 1

Clinical application errors:

• Using orthobiologics in severe osteoarthritis where evidence shows worse treatment response 2
• Failing to exhaust proven first-line treatments before considering biologics 2
• Not documenting preparation methods, making outcome assessment impossible 1

Safety oversights:

• Exceeding safe cell dosing thresholds (>4×10^6/kg) 6
• Using frozen-thawed cells without understanding increased adverse event risk 6
• Failing to perform blood compatibility testing before stem cell administration 6

Future Directions

The consensus identifies knee osteoarthritis as the "serious condition" with most urgent need for clinical trial development. 1 High-quality multicenter randomized controlled trials with standardized preparation protocols, biorepositories, and validated outcome measures are essential. 1, 2, 8

International models being explored:

• Japan's provisional approval pathway (grant approval for safe products showing potential effect, withdraw if efficacy not demonstrated in postmarket surveillance) 1
• Chile's public-private partnership using culture-expanded bone MSCs with registry-based outcomes tracking 1

Until rigorous evidence emerges, the professional consensus is clear: orthobiologics should not be routinely offered, and when used, must be accompanied by transparent communication about their unproven status and commitment to systematic outcome tracking. 1, 2