Orthobiologics - MS Orthopaedics (20 Marks)

Definition

Three Fundamental Mechanisms of Action

• Rockwood and Green's Fractures in Adults, 10th Ed, p.91

Classification of Orthobiologics (Laurencin Classification)

1. Allograft-based - allograft bone, with or without other elements
2. Factor-based - natural and recombinant growth factors (rhBMP-2)
3. Cell-based - MSCs, bone marrow aspirate concentrate (BMAC), PRP
4. Ceramic-based - calcium phosphate, calcium sulfate, bioactive glass
5. Polymer-based - biodegradable and non-degradable polymers
6. Miscellaneous - coralline hydroxyapatite (coral/sponge skeleton)

• Campbell's Operative Orthopaedics, 15th Ed, p.3277

1. Bone Grafts

A. Autograft

• Gold standard, possessing all three properties: osteoinductive, osteoconductive, osteogenic
• No risk of histoincompatibility or disease transmission
• Types:
  • Cancellous autograft (iliac crest): large surface area, rapid incorporation, high pluripotent cell density - but low structural integrity
  • Cortical autograft: high structural integrity, delayed incorporation
• Iliac crest bone graft (ICBG): workhorse of autograft; harvested from anterior or posterior iliac crest
• Drawbacks: donor site morbidity (pain, cosmetic defect, fatigue fracture, heterotopic ossification), limited volume, increased anesthesia time and blood loss

B. Allograft

• Harvested from cadaveric donors; processed as fresh-frozen, freeze-dried, irradiated (electron beam/gamma ray), or decalcified
• Properties: osteoconductive + variable osteoinductive (but NOT osteogenic - no live cells)
• Forms: structural cortical struts (proximal humerus calcar support), morsellized bone extender, DBM
• Risks: disease transmission (Hepatitis B, C; bacterial infection), variable osteoinductive strength, graft rejection
• Demineralized Bone Matrix (DBM): decalcified allograft that retains osteoinductive proteins; supplied as putty, injectable gel, paste, powder, strips; may be mixed with bone marrow to add osteogenic cells. Considerable variability between products based on source, processing, carrier type

2. Bone Graft Substitutes

A. Ceramics

Calcium Phosphate

• Three forms: Hydroxyapatite (HA), Tricalcium phosphate (TCP), Calcium phosphate cement
• Resorption rates: HA slowest (>10 years on X-ray), TCP moderate (6-18 months), CPC achieves highest compressive strength
• Clinical evidence: RCT (Russell and Leighton) comparing CPC vs autograft in tibial plateau ORIF - better motion, less radiographic subsidence with CPC
• Used in distal radius, calcaneus, tibial plateau fractures

Calcium Sulfate

• Faster resorption than calcium phosphate
• Acts purely as osteoconductive scaffold
• Used as antibiotic carrier in infected bone (Osteoset beads)

B. Bioactive Glass

• Bonds to both hard and soft tissue; osteoconductive
• Less commonly used currently

3. Factor-Based Orthobiologics (Growth Factors)

A. Bone Morphogenetic Proteins (BMPs)

• BMP was first identified by Urist in 1965 as able to induce endochondral bone formation
• BMPs are part of the TGF-β superfamily (transforming growth factor beta)
• Over 20 BMPs identified; only two clinically available:
  • rhBMP-2 (recombinant human BMP-2): FDA-approved for open tibial fractures (with IM nail), anterior lumbar interbody fusion, acute mandibular reconstruction
    • Govender et al. RCT (450 patients, J Bone Joint Surg Am, 2002): rhBMP-2 reduced infection rates and accelerated fracture healing in open tibial fractures
  • rhBMP-7 (OP-1): was approved under Humanitarian Device Exemption for revision spinal fusion and recalcitrant tibial nonunion - subsequently withdrawn from market
• BMP-2 and BMP-7 are water soluble - require a carrier (collagen sponge) to remain at the operative site
• Other BMPs with osteogenic properties: BMP-4, -6, -9
• In congenital pseudarthrosis of tibia: rhBMP used as adjunct to intramedullary fixation with favorable early union rates

B. Other Growth Factors

4. Cell-Based Orthobiologics

A. Platelet-Rich Plasma (PRP)

• A concentration of platelets and growth factors (PDGF, TGF-β1, VEGF, EGF, FGF) derived from autologous whole blood by centrifugation
• Mechanism: platelets degranulate and release alpha-granules containing growth factors, initiating the healing cascade
• Preparation: blood centrifuged in two stages - first to separate red blood cells, second to concentrate platelets (typically 3-5x baseline concentration)
• Applications in orthopaedics:
  • ACL reconstruction (augmentation - evidence inconclusive)
  • Meniscal repair (especially avascular zone)
  • Rotator cuff repair
  • Lateral epicondylitis (tennis elbow) - Level I evidence showing benefit
  • Plantar fasciitis
  • Knee osteoarthritis (intra-articular injection)
  • Non-union treatment
• Current evidence: "No studies have definitively shown an enhanced healing response or improved results when orthobiologics are added to intraarticular ACL reconstructions" (Campbell's, 15th Ed)
• Marrow stimulation or orthobiologics can be utilized as an adjunct to augment meniscal repair (Campbell's)

B. Bone Marrow Aspirate Concentrate (BMAC)

• Harvested from iliac crest (posterior preferred) by percutaneous aspiration
• Contains MSCs, hematopoietic stem cells, growth factors
• Concentration step (centrifugation) enriches MSC/progenitor cell content
• Used in: fracture non-union, osteonecrosis, cartilage defects, tendon/ligament augmentation
• Advantage: single-stage, minimally invasive, no ex vivo manipulation required

C. Mesenchymal Stem Cells (MSCs)

• Pluripotent stromal cells capable of differentiating into osteoblasts, chondrocytes, adipocytes, tenocytes
• Sources: bone marrow, adipose tissue, synovium, periosteum
• Can be used alone or combined with scaffolds (allograft + BMAC = osteogenic construct)
• Tissue engineering applications: seeded onto biodegradable scaffolds for large bone defect reconstruction

5. Physical/Biophysical Enhancement (Related Modalities)

6. Clinical Applications Summary

7. Advantages and Limitations

Key Points for Exam

1. Urist (1965) - discovered BMP and its ability to induce endochondral bone formation
2. Autograft (ICBG) remains the gold standard for all three properties (osteoinductive + osteoconductive + osteogenic)
3. Only rhBMP-2 is currently FDA-approved for clinical use in humans; rhBMP-7 was withdrawn
4. DBM contains osteoinductive proteins but variability is high between products
5. PRP delivers a supraphysiologic concentration of growth factors but evidence for most orthopaedic applications remains Level II-III
6. Ceramics (HA, TCP) are purely osteoconductive scaffolds
7. The three mechanisms - osteoinduction, osteoconduction, osteogenesis - must be understood in relation to every graft type
8. Physical modalities (LIPUS, electrical stimulation, ESWT) complement biologic orthobiologics in fracture healing

• Rockwood and Green's Fractures in Adults, 10th Ed (2025), Chapter 3 - Enhancement of Fracture Healing, pp. 91-92 (Osteoinduction, Osteoconduction, Osteogenesis, Autograft, Allograft, Bone Graft Substitutes, Cell-based Therapies, Growth Factors)
• Campbell's Operative Orthopaedics, 15th Ed (2026), Chapter 58 - Bone Graft Substitutes, pp. 3277-3278 (Laurencin classification, DBM, rhBMP-2, Ceramics); Chapter 31 (rhBMP in congenital pseudarthrosis)
• Govender et al. JBJS 2002 - rhBMP-2 for open tibial fractures (450-patient RCT)