Assessing clinical implications and perspectives of the pathophysiological effects of erythrocytes and plasma free hemoglobin in autologous biologics for use in musculoskeletal regenerative medicine therapies. A review

Abstract

Autologous biologics, defined as platelet-rich plasma (PRP) and bone marrow aspirate concentrate (BMC), are cell-based therapy treatment options in regenerative medicine practices, and have been increasingly used in orthopedics, sports medicine, and spinal disorders. These biological products are produced at point-of-care; thereby, avoiding expensive and cumbersome culturing and expansion techniques. Numerous commercial PRP and BMC systems are available but reports and knowledge of bio-cellular formulations produced by these systems are limited. This limited information hinders evaluating clinical and research outcomes and thus making conclusions about their biological effectiveness. Some of their important cellular and protein properties have not been characterized, which is critical for understanding the mechanisms of actions involved in tissue regenerative processes. The presence and role of red blood cells (RBCs) in any biologic has not been addressed extensively. Furthermore, some of the pathophysiological effects and phenomena related to RBCs have not been studied. A lack of a complete understanding of all of the biological components and their functional consequences hampers the development of clinical standards for any biological preparation. This paper aims to review the clinical implications and pathophysiological effects of RBCs in PRP and BMC; emphasizes hemolysis, eryptosis, and the release of macrophage inhibitory factor; and explains several effects on the microenvironment, such as inflammation, oxidative stress, vasoconstriction, and impaired cell metabolism.

Platelet Concentrates in Musculoskeletal Medicine

“…Red Blood Cells (RBCs) can be damaged as a result of high shear force during blood collection or during inadequate centrifugation process, so causing hemolysis with the release of hemoglobin and its degradation products, hemin and iron. The presence of these hemolytic-related products lead to several deleterious effects, such as radical oxygen reactions, endothelial disfunction, vascular endothelium damage, pro-inflammation response and tissue injury [90].…”

“…RBC damage also causes the release of migration inhibitory factor (MIF), which has been recognized as a very strong inflammatory cytokine [90]. MIF concentration in whole blood is 1000-fold increased than in plasma.…”

Isolation, Activation, and Mechanism of Action of Platelet-Rich Plasma and Its Applications for Joint Repair

“…In fact, several studies have reported that an excessive concentration of platelets may have inhibitory effects on cell proliferation or differentiation in populations such as tenocytes or adipose tissue-derived stem cells. Thus, the optimal platelet concentration for an optimized function is considered two-to threefold compared to blood levels [34,35].…”

“…The presence of erythrocytes in the PRP entails their own degradation processes such as hemolysis and eryptosis. As a result, products that promote inflammation and cellular stress are generated, which would hinder the beneficial action of PRP [38].…”

The Rationale of Autologously Prepared Bone Marrow Aspirate Concentrate for use in Regenerative Medicine Applications

“…Throughout the aspiration procedure, RBCs can be damaged as a result of high shear forces [108]. As a consequence, the RBC membrane will start to disintegrate, and hemolysis, with the release of PFH, will occur.…”