Benefits of STABHA™ in Soft Tissue Injuries – ligaments and tendons

What is STABHA™? STABHA™ - Soft Tissue Adapted Biocompatible Hyaluronic Acid Soft tissue adapted because of its high biocompatibility High biocompatibility is a result of its purity profile Purity profile is achieved with an exclusive patented manufacturing process

How does STABHA™ work in ligament injury (e.g. in an ankle sprain)?

Physiopathology of ligament sprains Acute inflammatory/bleeding phase: From minutes of injury to the next 48 to 72 hours. Clot formation begins. The platelet-rich fibrin clot releases growth factors and provides a platform on which many cellular events occur. Proliferative phase: Fibroblast proliferation signals for rebuilding the ligament tissue matrix (initially appears as disorganized scar tissue and extracellular matrix begins a turnover process). The collagen becomes aligned with the long axis of the ligament during this time; however, the newly-formed collagen fibrils are abnormal and smaller in diameter than normal ligament tissue. Remodelling phase: After a few weeks collagen maturation begins. With time (several months) the tissue matrix starts to resemble normal ligament tissue; however, critical differences in matrix structure and function persist.

Mechanism of action of STABHA™ in ligament sprains (1) In acute phase (up to 48 to 72 hours): Inflammation (and bleeding) is present. When injury occurs: fibrin (blood’s component) is present and body increase hyaluronic acid production. Injection forms a gel-like STABHA™- fibrin complex into the injury site giving a larger hydrodynamic volume in situ acting as a cushion for physical support (scaffold effect). Provides support internally. Increases cell proliferation and reduces inflammation.

Mechanism of action of STABHA™ in ligament sprains (2) In addition to the STABHA™– fibrin complex, STABHA™ also serves as: Better healing quality. Less scar tissue formation. Lubrication (hydrodynamic volume) to reduce adhesion allows better structural configuration of fibres (faster reconstruction and recovery).

How does STABHA™ work in tendon injuries (chronic)?

Tendon structure A tendon is a structure with strong tensile strength due to its components and how there are organised in parrallel bundles These fibres are surrounded by a substance called ECM (extra-cellular matrix) which in turn contains PGs (proteoglycans). The ECM and PGs contain HA that naturally exists In the injured tendon, there is a disorganisation of the above structure, which will no longer be in parrallel arrangement and then will no longer be able to glide over each other freely to allow motion and use. It is called tendinopathy. The strength and mobility will also be reduced.

Tendon injury and healing (1) When a tendon is injured, it will naturally try to heal. This is known as proliferative stage

Tendon injury and healing (2) Proliferative stage The continued recruitment of fibroblasts and their rapid proliferation at the wound healing site are responsible for the synthesis of collagens, PGs and other components of the ECM. These components are initially arranged in a random manner within the ECM, which at this point is composed largely of type III collagen. An extensive blood vessel network is present, and the wound has a scar-like appearance. At the end of the proliferative stage, the repair tissue is highly cellular and contains relatively large amounts of water and an abundance of ECM components. Collagen type-III is gradually replaced by type-I collagen as the scar tissue matures.

Tendon injury and healing (2) – Flow charts version

The importance of HA in tendon healing (1) In the ECM: HA helps in maintaining a good quality of ECM surrounding the tendon HA creates an ideal environment that improves lubrication and nutrition of the cells with the tendon

The importance of HA in tendon healing (2) HA allows more proteoglycans to form HA stimulates tenocytes and tenoblasts thereby increasing collagen production HA stimulates the conversion of collagen type III (unhealthy tendon, see image 1) into collagen type I (healthy tendon, see image 2) Image 1 Image 2

Mechanism of action of STABHA™ in tendon injury STABHA™ is the supplementation of biocompatible HA to the injury site. Improves quality of extracellular matrix Provides lubrication for fibril movement Allows realignement of collagen type III to reform into type I Corrects fibres position allowing optimal configuration = reduces adhesions of scar tissue Provides quicker/better repair (limiting inflammation and decrease in pain) Increases rate of repair. Improves and restores strength and increases range of motion

Conclusion STABHA™ is a biocompatible form of Hyaluronan STABHA™ is able to help patients with soft tissue injuries (of ligaments and tendons) recover FASTER and BETTER STABHA™ is able to help reducing pain experience from soft tissue injury STABHA™ improves quality of healing thereby reducing recurrences in ankle sprains, or maintains use of tendons in shoulders and elbows STABHA™ is localised and targeted treatment for injuries that are currently only managed by standard of care STABHA™ improves the tensile strength and might reduce scar tissue formation STABHA™ allows to have earlier return to mobility

References G. Schulze-Tanzil et al. Decellularized Tendon extracellular Matrix. A Valuable Approach for Tendon Reconstruction? Cells 2012, 1, 1010-1028 N. Maffulli et al. The Achilles Tendon. Springer S. Dholariya. GAG & Proteoglycans Graham Hugh Thomas. The Organization of Cells in Tissue – The Extracellular Matrix, Cell Junctions and Cell Adhesion. Osti et al. Hyaluronic acid increases tendon derived cell viability and collagen type I expression in vitro: Comparative study for four different hyaluronic acid preparations by molecular weight. BMC Musculoskeletal Disorders; 2015 Hausel et al. The open rehabilitation Journal. 2013; 6:1-20 Weiss et al. Musculoskeletal applications of hyaluronan and hylan. Potential uses in the foot and ankle. Clin Pediatr Med Surg; 1995 Riley et al. The pathogenesis of tendinopathy. A molecular perspective. Rheumatology 43 (2): 131-142 James et al. Tendon: Biology, biomechanics, repair, growth factors and evolving treatment options. Review article, 2008 Sharma et al. Tendon injury and tendinopathy: healing and repair. Bone Joint Surg Am.87: 187-202; 2005 Khan et al. The painful nonruptured tendon: clinical aspects. Clin Sports Med 22 (2002):711-725 Skirven et al. Rehabilitation of the Hand and Upper Extremity. 6th edition published by Elsevier Hamada et al. Intrinsic healing capacity and tearing process of torn supraspinatus tendons: In situ hybridization study of ά1 procollagen mRNA. J. Orthop. Res. Vol 15; 1997