Innovative regenerative medicine in the management of knee OA: The role of Autologous Protein Solution

Abstract

Osteoarthritis (OA) is one of the most common causes of chronic disability in adults due to pain and altered joint function. Although most patients report pain and functional limitation, symptoms, age of onset and disease progression are extremely variable. While inflammation could play a central role in the OA pathogenesis and progression, many underpinning mechanisms are still unclear. A number of proinflammatory mediators have been found in OA joints and could play a role, such as IL-1, IL-6, IL-7, IL-8, IL-15, IL-17, IL-18, TNF-alpha, macrophage chemotactic protein (MCP)-1, interferon-induced protein (IP)-10, monokine induced by interferon (MIG), oncostatin M (OSM), growth-related oncogene (GRO)alpha, chemokine (C-C-motif) ligand 19 (CCL19), macrophage inflammatory protein (MIP)-1beta, and TGF-alpha. Biological approaches have recently got increasing interest due to their anti-inflammatory and immunomodulatory properties, regenerative potential, and high tolerability. The primary aim of this paper is to report the current concepts on regenerative medicine for knee OA with a particular focus on Autologous Protein solution (APS). APS is a blood derived product obtained by using a proprietary device, made of APS Separator, which isolates WBCs and platelets in a small volume of plasma, and APS Concentrator, which further concentrates platelets, WBCs and plasma proteins. The result is a peculiar formulation differing from other biologic products as it contains high levels of growth factors (EGF, IGF-1, PDGF-AB, PDGF-BB, VEGF, TGF-b1) along with high concentrations of anti-inflammatory mediators (IL-1ra, sIL-1RII, sTNF-RI, sTNF-RII) and low levels of pro-inflammatory cytokines (Il-1b and TNF-a). While emerging evidence supports the use of APS, as confirmed by in vitro studies and preliminary clinical results, the real clinical potential of APS and its benefits are still under investigation.

Autologous cell-free serum preparations in the management of knee osteoarthritis: what is the current clinical evidence?

“…To date, the outcomes of 1229 patients involved in studies evaluating the effect of injection of ACS/APS have been reported ( Table 2). The adverse reactions noted in these patients have been similar to the intraarticular administration of other therapeutic agents [17,40]. Additionally, they have been of a transient and self-limiting type [12,41].…”

“…In general, both ACS and APS are prepared from autologous peripheral blood, the volume of which can vary between 10 and 60 ml depending on the manufacturer kit [20,37,38]. The obtained blood sample is further conditioned by incubation with glass beads and centrifugation, leading to an increase in the production of IL-1Ra as well as multiple other cytokines and growth factors [17,20].…”

“…However, dose-dependent chondrotoxicity [11], short duration of effect [12] with IAC and arthralgia [13], and variable evidence [14] with HA are some of their limitations. Some investigators have performed intraarticular injection of platelet-rich plasma (PRP) [15] and mesenchymal stem/stromal cells (MSCs) [16] due to their perceived biological function(s) to restore joint homeostasis [12,17]. The pathophysiology of OA includes a complex interplay of pro-inflammatory mediators like interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-a), macrophage chemotactic protein (MCP), monokine induced by interferon (MIG), oncostatin M (OSM) and matrix metalloproteinases (MMPs) amongst others.…”

“…The pathophysiology of OA includes a complex interplay of pro-inflammatory mediators like interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-a), macrophage chemotactic protein (MCP), monokine induced by interferon (MIG), oncostatin M (OSM) and matrix metalloproteinases (MMPs) amongst others. The biological therapeutic group products which have been developed for the management of OA of the knee are designed to inhibit the action of interleukin-1 (IL-1), a pro-inflammatory cytokine that has been implicated in, and targeted for treatment of, multiple human diseases [12,17,18]. Animal experimental evidence suggests that upregulation of IL-1-receptor antagonist (IL-1Ra) may reduce the progression of OA [19].…”

“…Animal experimental evidence suggests that upregulation of IL-1-receptor antagonist (IL-1Ra) may reduce the progression of OA [19]. Biological injective therapy options based around this theory have been developed and referred to as autologous conditioned serum (ACS) or autologous protein solution (APS), both of which are prepared from autologous peripheral blood, which is conditioned by incubation with glass beads, leading to increases in the production of IL-1Ra as well as multiple other cytokines and growth factors [17].…”