A Novel Regenerative Tissue Matrix (RTM) Technology for Connective Tissue Reconstruction
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The goal of regenerative medicine is to recapitulate in adult wounded tissue the intrinsic regenerative processes that are involved in normal adult tissue maintenance. Recent advances allow adult wounds to heal in a similar fashion to the regenerative healing that is also present during fetal development. Research suggests that tissue loss or injury that occurs during early fetal development can be corrected by a regenerative mechanism since fetal wound healing appears to occur without scar formation.1 However, later in the gestational development there is a transition from the regenerative to the reparative healing process, which utilizes fibrosis and scar formation to replace damaged or otherwise wounded connective tissue. Scar does not have the native structure, function, and physiology of the original normal tissue.
When a wound exceeds a critical deficit it requires a scaffold to organize tissue replacement, and 3 pathways or mechanisms of action may exist for the body to respond to the implanted material (Figure 1). A synthetic material or an extracellular matrix (ECM) that has been intentionally crosslinked to avoid enzymatic degradation will elicit a foreign body response towards the implant resulting in encapsulation. Foreign bodies have an increased potential for long-term infection and extrusion of the implant. When a temporary, resorbable synthetic or a poorly processed ECM is employed for wound closure, an inflammatory response will result in resorption of the implant with the deposition of a reparative scar to close the wound. In contrast, a regenerative tissue matrix (RTM), comprising a structurally and biochemically intact ECM implanted at the wound site, supports the appropriate cascade of cellular events characteristic of tissue regeneration ultimately leading to remodeling and transition of the RTM to tissue resembling that which was lost. Therefore, it is critical to understand these differing mechanisms of action in order to understand how the process for preparing the ECM determines which mechanism of action will be utilized by the body.
While regenerative healing is characterized by the restoration of the structure, function, and physiology of damaged or absent tissue, reparative healing is characterized by wound closure through scar formation. Reparative healing begins with the deposition of a provisional protein scaffold of fibrin as a result of hemostasis. Although transitory in nature, this fibrin scaffold serves to organize the healing process through several functional activities.2 Initial platelet activation triggers a release of growth factors and other morphogens that become deposited within the fibrin scaffold. In addition to the immobilized growth factors, this scaffold contains cell adhesion proteins that exhibit specific binding to a variety of integrin receptors found on the surface of inflammatory fibroblasts and lymphocytes. These interactions coupled with accommodative protease activity stimulate cell migration into the scaffold. The eventual fibrinolysis and matrix elaboration by the cells within the provisional scaffold along with vascularization of this new connective tissue ultimately results in scar tissue formation. This tissue has a characteristic structure, cellularity, and vascular pattern that are clearly distinguishable from the original, native connective tissue prior to injury. While scar tissue often serves a critical role in the survival of an organism, clinically it is considered a pathological state exhibiting suboptimal functional, biomechanical, and physiological characteristics compared to normal, native connective tissue.
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