OPBSMusculoskeletalPharmacology

Must Know

Adult articular cartilage has a poor intrinsic repair response.
Cartilage is mostly avascular and fed by diffusion from synovial fluid, so a laceration does not bleed.
Chondrocytes are trapped in dense matrix and migrate poorly to injury.
Damaged cartilage releases too little chemotactic signal to recruit repair cells.
Collagen II resists tension. Aggrecan gives osmotic pressure and compressive resistance.
Repair strategies combine cells, signals and scaffolds.
Strategies are grouped by mode of action (mechanical or biological) and delivery (systemic, local, surgical).
Repair targets focal defects and osteoarthritis.

Strategy	Aim	Example
Augmentation	Tissue that eases pain and restores some function, often fibrous	Microfracture
Regeneration	Reform normal hyaline cartilage	ACI
Replacement	Graft containing articular cartilage	Osteochondral autograft or allograft
Substitution	Nonliving prosthesis	Joint replacement

Defects and Osteoarthritis

Partial-thickness defects stay in cartilage. Full-thickness reach calcified cartilage or subchondral bone. Osteochondral defects involve bone.
Treatment choice depends on size, location, surrounding cartilage, age, activity, obesity, malalignment and instability.
Hinge joints (knee, ankle, finger) and spheroidal joints (hip, shoulder) are the current repair targets.
OA prevalence rises with age and is higher in women.
In early OA, chondrocyte repair is offset by MMPs, aggrecanases, senescence and apoptosis.
Subchondral sclerosis, cysts, marrow lesions and osteophytes often precede late cartilage loss.
ICRS arthroscopic grades run 0 normal, 1 nearly normal, 2 abnormal, 3 and 4 severely abnormal by depth.

Nonsurgical Treatment

NSAIDs and analgesics relieve symptoms without modifying cartilage.
Long-term trials show limited effect of glucosamine and chondroitin.
Synovial permeability rises after injury and in OA, shortening intra-articular drug residence.
Evidence for hyaluronic acid viscosupplementation improving function is limited.
Intra-articular long-acting steroid effect fades after 1 week.

Surgical Options

Procedure	Defect size	Repair tissue	Points
Microfracture	Under 2 cm²	Fibrocartilage, more type I collagen	Single stage, cheap, first line
ACI	Over 2 cm², full thickness	Aims for hyaline	Two stages, costly, fragile early repair
Osteochondral autograft	1 to 4 cm²	Hyaline survives	Limited by donor site
Osteochondral allograft	Over 2 cm²	Hyaline survives, bone replaced by host	Cost, supply, disease transmission

Microfracture was developed by Steadman in the 1980s, with awl holes about 3 mm apart.
Marrow clot brings stem cells and growth factors into the defect.
Patients over 40 had worse microfracture repair scores with later deterioration.
AMIC adds a scaffold to microfracture in one stage. BST-CarGel bettered microfracture alone at 12 months.
ACI was developed by Brittberg in the 1990s. Biopsy of 200 to 300 mg comes from a non-load-bearing area.
Autograft beat microfracture for return to sport and failure rate in a review of 607 patients.
Autograft donor holes fill with cancellous bone capped by fibrocartilage by 8 weeks.
Allograft bone acts as an osteoconductive scaffold replaced by creeping substitution.
Allografts are stored up to 28 days and lavaged to remove marrow.
Freezing, prolonged storage and repeated impaction during insertion reduce chondrocyte viability.

ACI generation	Distinguishing feature
First	Cell suspension under a sutured periosteal flap from distal femur or proximal tibia
Second	Collagen membrane replaces periosteum
Third (MACI, MACT)	Cells seeded on a scaffold, fixed with fibrin glue or sutures
Fourth	Bioreactor or spheroid culture to build matrix and keep phenotype

Altering Joint Mechanics

HTO unloads the medial compartment in isolated medial OA.
HTO failure links to older age and advanced bone attrition.
Joint distraction uses an external fixator for up to 12 weeks, reported in hip, knee and ankle.
Distraction lowers subchondral density but raises density in cystic areas, with hyaline-like resurfacing in the ankle.
Distraction complications come from the frame, such as pin tract infection, thrombosis and neurapraxia.
Revision risk after joint replacement is inversely related to age at primary surgery.

Emerging Strategies

MSCs come mainly from bone marrow or fat, autologous or allogeneic.
As of 2018 no MSC therapy was authorised in the United States or Europe.
Cartistem is allogeneic umbilical cord MSCs placed into drill holes, approved in Korea.
TissueGene-C is allogeneic chondrocytes transduced to express TGF-β1, injected intra-articularly.
Chondrogenic signals include TGF-β, FGF, BMP and IGF families, many present in PRP.
IL-1 rises after acute knee injury. Anakinra, an IL-1 receptor antagonist, reduced early pain.
Dense charged matrix limits drug penetration into cartilage.

Numbers to Remember

Composition. Chondrocytes about 2 percent by volume, matrix 20 to 40 percent, water 60 to 80 percent by weight.
Matrix. Collagen II about 200 mg per g, proteoglycan about 25 mg per g wet weight.
Hand OA over 55. 67 percent of women, 55 percent of men.
Knee OA over 80. 53 percent of women, 33 percent of men.
Allograft at 5 years. 86 percent satisfaction, 2.4 percent short-term complications.
HTO survival at 10 years. 50 to 95 percent.

Exam Traps

Microfracture repair is fibrocartilage with more type I collagen than hyaline cartilage.
First-generation ACI used periosteum. Collagen membrane defines second generation.
In allografts the cartilage survives while the bone is replaced by host bone.
Joint distraction lowers general subchondral bone density yet raises density in cystic areas.

Recent Review. Mesenchymal Stromal Cells for Chondral Defects

Caplan coined mesenchymal stem cell in 1991. He later proposed medicinal signalling cell to match their real behaviour.
The ISCT term mesenchymal stromal cell reflects multipotent cells lacking proven self-renewal in vivo.
In vivo, MSCs act mainly as trophic mediators, rarely engrafting or differentiating into new tissue.
MSCs secrete VEGF, IL-6 and G-CSF, which dampen local immune response and stimulate resident repair cells.
MSCs make up about 1 in 10000 to 20000 marrow cells and about 1 in 2000 adipose cells.
Bone marrow is harvested from iliac crest, proximal humerus, proximal tibia or calcaneus. Fat comes from liposuction or infrapatellar pad.
The FDA permits only minimally manipulated cells, excluding enzymatic digestion and culture expansion.
Marrow stimulation produces fibrocartilage with less type II collagen and inferior mechanics to hyaline cartilage.
MSC-augmented microfracture improved MRI and histology scores, with little consistent clinical benefit (grade I evidence).
Current MSC preparations appear symptom modifying more than structure modifying.

Source

Gacasan EG, Sah RL. Articular Cartilage Repair. Augmentation, Regeneration, Replacement, and Substitution. In. Aaron RK, editor. Orthopaedic Basic Science. Foundations of Clinical Practice. 5th ed. Philadelphia, Wolters Kluwer, 2021.

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Reviewed by Professor Phong Tran, Head of Orthopaedic Surgery, Western Health. Last updated 17 October 2026.