Platelet‐like particles reduce coagulopathy‐related and neuroinflammatory pathologies post‐experimental traumatic brain injury

Abstract

Coagulopathy may occur following traumatic brain injury (TBI), thereby negatively affecting patient outcomes. Here, we investigate the use of platelet‐like particles (PLPs), poly(N‐isopropylacrylamide‐co‐acrylic‐acid) microgels conjugated with a fibrin‐specific antibody, to improve hemostasis post‐TBI. The objective of this study was to diminish coagulopathy in a mouse TBI model (controlled cortical impact) via PLP treatment, and subsequently decrease blood–brain barrier (BBB) permeability and neuroinflammation. Following an acute intravenous injection of PLPs post‐TBI, we analyzed BBB permeability, ex vivo coagulation parameters, and neuroinflammation at 24 hr and 7 days post‐TBI. Both PLP‐treatment and control particle‐treatment had significantly decreased BBB permeability and improved clot structure 24 hr post‐injury. Additionally, no significant change in tissue sparing was observed between 24 hr and 7 days for PLP‐treated cohorts compared to that observed in untreated cohorts. Only PLP‐treatment resulted in significant reduction of astrocyte expression at 7 days and percent difference from 24 hr to 7 days. Finally, PLP‐treatment significantly reduced the percent difference from 24 hr to 7 days in microglia/macrophage density compared to the untreated control. These results suggest that PLP‐treatment addressed acute hypocoagulation and decreased BBB permeability followed by decreased neuroinflammation and fold‐change tissue loss by 7 days post‐injury. These promising results indicate that PLPs could be a potential therapeutic modality for TBI.

Polymeric particle-based therapies for acute inflammatory diseases

“…Deformable particles can also be used to mimic cells, such as platelets, for therapeutic applications. For example, despite showing great potential for treating coagulopathic diseases (in which clotting does not occur fast enough) 185 , 186 , platelet transfusions can still result in immunogenic side effects 187 . Poly( N -isopropylacrylamide- co -acrylic-acid) microgel particles (1 µm) conjugated to a fibrin antibody can mimic the size, morphology and fibrin binding of platelets 187 .…”

“…For example, despite showing great potential for treating coagulopathic diseases (in which clotting does not occur fast enough) 185 , 186 , platelet transfusions can still result in immunogenic side effects 187 . Poly( N -isopropylacrylamide- co -acrylic-acid) microgel particles (1 µm) conjugated to a fibrin antibody can mimic the size, morphology and fibrin binding of platelets 187 . These platelet-like particles increase clot formation and stability in traumatic brain injuries, preventing post-traumatic neuroinflammation.…”

“…These platelet-like particles increase clot formation and stability in traumatic brain injuries, preventing post-traumatic neuroinflammation. Additionally, they have a longer shelf life compared to natural platelets, with potential applicability for treating other haemorrhagic bleeding disorders that lead to downstream inflammation 187 .…”

Intravenous Hemostats: Foundation, Targeting, and Controlled-Release

“…The in vitro experimental results show that the amount of fibrinogen formed by PLPs added to platelet-enriched plasma (PPP) is similar to that formed by platelet-enriched plasma (PRP) (Figure 11A(c)); recently, the research team has further studied the role of PLPs in traumatic brain injury. 80 The results show that, compared with the control group, PLPs injection can significantly reduce the permeability of the blood−brain barrier 24 h after injury and improve the structure of the clot, and can dramatically reduce the percentage difference of glial cell/macrophage density 24 h to 7 days after injury. In addition, compared with the treatment group without PLPs, no significant wound changes were observed in the PLPs treatment group between 24 h and 7 days, all of which suggests that PLPs are an effective intravenous hemostat.…”

“…(B) The polySTAT; part a is the molecular structure, part b is the SEM images of the full fibrin clots in the presence of PolySCRAM or PolySTAT, and part c is the results of the hemorrhage rate in the rat artery injury model . Reproduced with permission from ref . Copyright 2015 The American Association for the Advancement of Science.…”