Clinical trials have been performed to assess the safety and efficacy of ADMSC therapy for knee osteoarthritis, and the findings have been promising. But additional work is necessary to establish the best dosing regimen and timing of ADMSC therapy and to assess its long-term safety and efficacy.

ADMSCs are generally harvested through a minimally invasive liposuction technique to acquire adipose tissue from the patient’s body. The acquired tissue is processed to separate the stem cells through emulsification and centrifugation.

This process is done by taking a small sample of the patient’s adipose tissue, processing it to separate the regenerating cells, and re-injecting the fat that has been enriched in the patient’s body in this example into the Knee joints.

Types of Cells in ADMSC (Adipose-Derived Mesenchymal Stem Cells) and Their Functions

The cell population of ADMSCs comprises different types of cells, each of which plays a specific role in regeneration and repair of the tissue.

• Mesenchymal Stem Cells (MSCs)
  Function: Multipotent cells with the ability to differentiate into osteocytes (bone cells), chondrocytes (cartilage cells), adipocytes (fat cells), and myocytes (muscle cells).
  Regenerative Role: MSCs produce cytokines and growth factors that regulate the immune response, stimulate angiogenesis (formation of new blood vessels), and aid tissue repair.
• Endothelial Progenitor Cells (EPCs)
  Function: Precursors to endothelial cells with a role in vascular repair.
  Regenerative Role: Facilitate neovascularization and the formation of blood vessels, improving tissue oxygenation and healing.
• Pericytes
  Function: Pericytes are supportive cells that cover blood vessels and modulate blood flow.
  Regenerative Role: Maintain vascular stability, regulate endothelial cell proliferation, and play a role in immune modulation.
• Pre-Adipocytes
  Function: Precursor cells that mature into adipocytes.
  Regenerative Role: Offer structural support and energy stores while releasing adipokines that affect tissue repair.
• Fibroblasts
  Function: Cells that produce collagen and extracellular matrix (ECM).
  Regenerative Role: Have a significant role in wound healing by secreting ECM components that allow tissue remodeling.
• Macrophages and Other Immune Cells
  Function: Regulate inflammatory responses and debris clearance.
  Regenerative Role: Certain macrophages (M2 phenotype) reduce inflammation and enhance healing by secreting anti-inflammatory cytokines.

ADMSCs release a number of growth factors and cytokines that stimulate regeneration by triggering cell proliferation, anti-inflammation, and vascularization. Some of the important growth factors released by ADMSCs during tissue repair are mentioned below:

• Vascular Endothelial Growth Factor (VEGF)
  Encourages formation of blood vessels (angiogenesis) and increases oxygen levels to tissues.
• Platelet-Derived Growth Factor (PDGF)
  Stimulates proliferation of cells and helps in repair of tissues by promoting fibroblast and MSC functions.
• Transforming Growth Factor-Beta (TGF-β)
  Controls immune response and wound healing by stimulating collagen production.
• Insulin-Like Growth Factor (IGF-1)
  Aids in tissue regeneration through the stimulation of cell growth and differentiation.
• Epidermal Growth Factor (EGF)
  Increases proliferation of epithelial cells and improves wound closure.
• Fibroblast Growth Factor (FGF-2)
  Stimulates fibroblasts, collagen synthesis, and tissue repair.
• Hepatocyte Growth Factor (HGF)
  Reduces inflammation, organ regeneration, and exerts anti-fibrotic action.
• Interleukins (IL-10, IL-6, IL-1RA)
  Controls immune reactions by lowering inflammation and aiding in tissue repair.
• Colony-Stimulating Factors (CSFs)
  Stimulate the growth of immune cells, promoting the healing process.

• Cartilage Repair
• Differentiate into chondrocytes to repair damaged cartilage, especially in osteoarthritis.
• Release anti-inflammatory cytokines that minimize pain and swelling in joints.
• Wound Healing & Skin Regeneration
• Induce collagen synthesis and new blood vessel formation.
• Minimize fibrosis and scarring.
• Bone Regeneration
• Differentiate into osteoblasts to contribute to bone repair.
• Increase bone mineralization and structural strength.
• Muscle Regeneration
• Assist in the repair of muscles by differentiating into muscle progenitor cells.
• Release growth factors that stimulate tissue repair following injury.
• Vascular Regeneration
• Increase the growth of new blood vessels, enhancing circulation in ischemic tissues.
• Maintain endothelial cell function to repair injured blood vessels.
• Immunomodulation
• Inhibit overactive immune responses, lowering inflammation in autoimmune diseases.
• Encourage an anti-inflammatory environment that boosts tissue regeneration.

Overview of Knee Osteoarthritis (OA)

Knee osteoarthritis (OA) is a degenerative joint disorder defined by:

• Progressive cartilage degeneration
• Synovial inflammation
• Subchondral bone remodeling
• Pain, stiffness, and loss of joint function

ADMSCs have been introduced as a new regenerative treatment for OA based on their anti-inflammatory, immunomodulatory, and cartilage-regenerating capabilities.

Overview of Knee Osteoarthritis (OA)

ADMSCs facilitate cartilage repair and joint function through various mechanisms:

• Chondrogenic Differentiation
  ADMSCs can differentiate into chondrocytes (cartilage-forming cells), facilitating cartilage regeneration.They are involved in the production of type II collagen and proteoglycans, which are necessary for cartilage structure.
• Anti-Inflammatory Effects
  OA is characterized by elevated levels of pro-inflammatory cytokines (IL-1β, TNF-α).ADMSCs produce anti-inflammatory cytokines (IL-10, TGF-β, IL-1RA) that neutralize inflammation.They minimize synovial inflammation and disease progression.
• Extracellular Vesicle and Growth Factor Secretion
  ADMSCs secrete exosomes and microvesicles with growth factors and miRNAs that guard chondrocytes and facilitate cartilage repair.

Primary growth factors include:

• Vascular Endothelial Growth Factor (VEGF): Increases blood supply to the joint.
• Transforming Growth Factor-β (TGF-β): Facilitates cartilage repair.
• Hepatocyte Growth Factor (HGF): Decreases fibrosis and inflammation.
• Fibroblast Growth Factor (FGF-2): Induces chondrocyte proliferation.

• Immunomodulation
  ADMSCs regulate the immune response by converting macrophages to an anti-inflammatory M2 phenotype, decreasing joint inflammation.They suppress the proliferation of T-cells and B-cells, decreasing auto-inflammatory responses.
• Subchondral Bone Remodeling
  OA impacts both cartilage and subchondral bone.ADMSCs release factors that activate osteoblasts, enhancing bone structure and stability.

Studies and Clinical Trials:

Several clinical trials have shown the efficacy of ADMSC therapy for knee OA:

• Pain Reduction: ADMSC therapy has been shown to significantly reduce pain scores (VAS, WOMAC scores).
• Functional Improvement: Patients show enhanced range of motion and less stiffness.
• Cartilage Repair: MRI and arthroscopy findings reveal greater cartilage thickness following ADMSC therapy.
• Long-Term Effects: Symptomatic improvement can persist for 12–24 months, with some patients needing further injections.

As of 2019, an estimated 364.6 million individuals around the world suffered from knee OA.
acrjournals.onlinelibrary.wiley.com
This accounts for approximately 4.9% of the total world population with a higher proportion in females (6.0%) than males (3.8%).
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While mechanical wear and aging are major contributors of knee OA, there are a number of additional factors that can contribute to increased risk:

While mechanical wear and aging are major contributors of knee OA, there are a number of additional factors that can contribute to increased risk:

• Obesity: Extra body weight places stresses on knee joints, promoting acceleration of cartilage breakdown.
• Genetics: A family history of OA predisposes individuals to the condition.
• Gender: Women are more likely to develop knee OA than men.
• Joint Injuries: Post-traumatic arthritis can result from previous injuries, including meniscal tears or ligament injury.
• Congenital or Developmental Disorders: Limb malformations or valgus or varus deformity predispose an individual to knee OA.
• Metabolic Disorders: Secondary knee OA is associated with diseases like hemochromatosis, chondrocalcinosis, ochronosis, Wilson’s disease, gout, pseudogout, acromegaly, and avascular necrosis.
• Inflammatory Arthritis: Rheumatoid arthritis, psoriatic arthritis, and infectious arthritis can all damage cartilage in the knee, resulting in OA.
• Occupational Factors: Prolonged standing, repetitive bending of the knee, or heavy lifting at work can contribute to developing knee OA.
• Muscle Weakness or Imbalance: Muscle weakness in the knee-supporting muscles can result in increased stress and degeneration of the joint.
• Infections: Infections of the joint can result in inflammation and damage, which can lead to OA.