Normal Ligament Healing Stages

•  Inflammation – Bleeding causes local swelling and clot formation. Inflammatory cells like M1 macrophages arrive to break down debris. Blood vessels grow into area. Lasts for 1-2 weeks.

• Proliferation – Fibroblasts migrate in to proliferate and lay down disorganized collagen matrix. Angiogenesis provides blood supply to support new tissue formation. Growth factors like TGF-beta and PDGF stimulate repair. Lasts for up to 6 weeks.

• Remodeling – Collagen fibers become aligned along lines of tension to improve function. Matrix gradually becomes more organized and ligament-like. Cellularity decreases. Lasts for months up to 1-2 years.

Current Therapies to Improve Healing

• Extracellular matrix patches – Porcine small intestine or other ECMs can be implanted at injury site to provide scaffold for cells.

• Growth factors – Injections of PRP, FGF, TGF-beta may stimulate cell proliferation and matrix synthesis. Repeated doses are likely needed.

• Stem cells – Endogenous ligament stem cells or bone marrow/adipose MSCs could be isolated and implanted locally at injury sites. Unclear best cell source.

• Biomaterials – Synthetic polymer or biological scaffolds seeded with stem cells may enhance structural support for healing.

•  Physical therapy – Controlled stretching and strength training helps direct new matrix alignment and build muscle support.

Nutrition and Supplement Considerations

• Articular refers to a joint or the joining of bones in the skeletal system.
• Intra-articular tissues are structures located inside the capsule of a joint, such as ligaments, menisci, cartilage, synovium.
• For example, the anterior cruciate ligament (ACL) and posterior cruciate ligament (PCL) in the knee are intra-articular ligaments.
• Extra-articular structures are outside the joint capsule, like muscles and tendons.
• Intra-articular ligaments and tissues are bathed in synovial fluid and exposed to the enclosed joint environment.
• This makes their blood supply more limited compared to extra-articular structures.

• M1 macrophages are considered classically activated and have pro-inflammatory properties.
• In tendon/ligament healing, M1s predominate during the early inflammatory phase, usually the first 1-2 weeks after acute injury.
• They phagocytose necrotic debris, pathogenic microbes, and damaged matrix at the injury site which helps prepare it for repair.
• M1s secrete pro-inflammatory cytokines like TNF-alpha, IL-1beta, IL-6 that amplify the inflammatory response.
• This recruits additional immune cells, increases vasodilation/permeability, and causes swelling.

• M2 macrophages are considered alternatively activated and have anti-inflammatory properties.
• In healing, M2s become more abundant as inflammation resolves, around 2-3 weeks post-injury.
• M2s secrete anti-inflammatory factors like IL-10. They block pro-inflammatory cytokine release.
• They promote angiogenesis, matrix deposition, and tissue remodeling.
• M2s allow the transition from the inflammatory phase to the regenerative proliferation phase.

• Angiogenesis is the process by which new blood vessels form from pre-existing vasculature.
• It predominantly occurs during the proliferative phase of healing, 2-6 weeks after injury.
• New blood vessel growth into the tendon/ligament injury site provides oxygen, nutrients, and essential growth factors needed for repair.
• Vascular endothelial growth factor (VEGF) is a key stimulator of angiogenesis. bFGF and TGF-beta also help drive new vessel formation.
• New vessels allow influx of reparative cells like fibroblasts needed for tissue regeneration.

• Fibroblasts are connective tissue cells responsible for producing and remodeling extracellular matrix like collagen.
• In tendon/ligament healing, extrinsic fibroblasts migrate into the wound 2-7 days after injury, peaking around 2 weeks.
• They proliferate, lay down disorganized type III collagen initially, and allow scaffolding for regeneration.
• Fibroblasts are key players in the proliferative phase, but may also mediate later remodeling by aligning collagen.

• The endotenon is a fine connective tissue sheath that envelops individual collagen fascicles (bundles) within a tendon.
• It contains the tendon's blood vessels, lymphatics, and nerve supply. These run longitudinally along the length of the tendon fascicles.
• The highly vascularized endotenon helps nourish the avascular collagen fibers and tenocytes within each fascicle.
• During tendon injury and healing, the endotenon is thought to be a source of extrinsic cells like fibroblasts and macrophages that migrate into the damaged region to facilitate repair.

• The epitenon is the outermost connective tissue sheath that envelops the entire tendon.
• It is made up of loose areolar connective tissue consisting primarily of type I and type III collagen fibers, as well as some elastic fibers.
• The epitenon contains the larger blood vessels, lymphatics and nerves that supply the entire tendon.
• It provides an interface between the tendon and surrounding tissues through which cells, growth factors, and nutrients can migrate into injured areas to stimulate healing.

• The paratenon is a sheath of loose connective tissue that surrounds an entire tendon.
• It consists of two layers - the visceral layer adheres to and covers the tendon, while the parietal (outer) layer forms an outer sleeve around the tendon.
• The paratenon contains some blood and lymphatic vessels that supply the tendon, but the main blood supply is in the epitenon.
• It reduces friction allowing smooth tendon gliding during movement. The paratenon may also facilitate diffusion of inflammatory cells and nutrients into injured tendons.