Exosomes derived from platelet-rich plasma administration in site mediate cartilage protection in subtalar osteoarthritis

Abstract

Subtalar osteoarthritis (STOA) is often secondary to chronic ankle sprains, which seriously affects the quality of life of patients. Due to its etiology and pathogenesis was not studied equivocally yet, there is currently a lack of effective conservative treatments. Although they have been used for tissue repair, platelet-rich plasma-derived exosomes (PRP-Exo) have the disadvantage of low retention and short-lived therapeutic effects. This study aimed to determine whether incorporation of PRP-Exo in thermosensitive hydrogel (Gel) increased their retention in the joint and thereby playing a therapeutic role on STOA due to chronic mechanical instability established by transecting lateral ligaments (anterior talofibular ligament (ATFL)/calcaneal fibular ligament (CFL)). PRP-Exo incorporated Gel (Exo-Gel) system, composed of Poloxamer-407 and 188 mixture-based thermoresponsive hydrogel matrix in an optimal ratio, was determined by its release ability of Exo and rheology of Gel response to different temperature. The biological activity of Exo-Gel was evaluated in vitro, and the therapeutic effect of Exo-Gel on STOA was evaluated in vivo. Exo released from Exo-Gel continuously for 28 days could promote the proliferation and migration of mouse bone mesenchymal stem cells (mBMSCs) and chondrocytes, at the same time enhance the chondrogenic differentiation of mBMSCs, and inhibit inflammation-induced chondrocyte degeneration. In vivo experiments confirmed that Exo-Gel increased the local retention of Exo, inhibited the apoptosis and hypertrophy of chondrocytes, enhanced their proliferation, and potentially played the role in stem cell recruitment to delay the development of STOA. Thus, Delivery of PRP-Exo incorporated in thermosensitive Gel provides a novel approach of cell-free therapy and has therapeutic effect on STOA. Graphical Abstract

The biological applications of exosomal-based materials in bone/cartilage tissue engineering

“…Moreover, the long-time controlled-release of pExos also could facilitate the chondrogenic differentiation of bMSCs and suppress inflammationinduced chondrocyte degeneration. (Zhang et al, 2022) 5 Advantages and challenges of exosomes in bone/cartilage tissue engineering…”

“…Enhancing cartilage tissue regeneration by activating Yes-associated protein (YAP) with the Wnt signaling pathwayTao et al (2017) MSCsPromoting cartilage repair by increasing proliferation, suppressing apoptosis, and modulating immuneZhang et al (2018) Attenuating inflammation and restoring matrix homeostasis, which could relieve TMJ osteoarthritisZhang et al (2019b) Combining with AD/CS/RSF hydrogel, promoting the cell migration, proliferation, and differentiation of bMSCs, and helping the repair of cartilage defectsZhang et al (2021) Combining with Gelatin methacrylate (Gelma)/nanoclay hydrogel, containing abundant miRNA-23a-3p and promoting cartilage regenerationHu et al (2020) Platelets Incorporating the pExos into thermosensitive hydrogel for prolonging the retention time of pExos in the joint, promotong the cell proliferation and migration of bMSCs and chondrocyteZhang et al (2022) …”

Functionalized Hydrogels for Cartilage Repair: The Value of Secretome-Instructive Signaling

“…The main reason for loading the secretome into a hydrogel, similar to what was discussed for GFs, is to prevent the immediate washout of the active molecules and prolong therapeutic exposure seeking better effectiveness on cartilage regeneration. Many hydrogels are composed of synthetic materials which are easily handled and adjusted, present more stable biochemical properties, and are less susceptible to batch-to-batch differences [ 136 , 137 ]. A recent study has demonstrated that a mixture of Poloxamer-407 and 188 is a functional injectable carrier to deliver platelet-rich plasma-derived exosomes (PRP-Exo) in an OA model.…”

“…The hydrogel could sustain the release of EXOs for about a month in vitro, and by using an imaging system, the authors confirmed the increase of PRP-Exo retention in the mice’s injured joint when the gel was applied. PRP-EXOs released from the hydrogel-PRP-EXOs complex remained functional, demonstrating positive effects on BM-MSC and chondrocytes in vitro and protective activity against inflammation-mediated apoptosis and degeneration of chondrocytes in vivo [ 136 ]. Another synthetic hydrogel potentially applied as a sustained-release delivery system was investigated by Tao and colleagues (2021) in OA models.…”

Platelet Rich Plasma in the Repair of Articular Cartilage Injury: A Narrative Review

“… 9 It has been reported that PRP exosomes also have protective effects on articular cartilage recently. 10 The main advantages of PRP for treatment of articular cartilage injury are simple production, high safety, minimal adverse reactions, and no foreign body rejection. 11 …”