Shoffstall Andrew, Li Longshun, Hartzler Aniya, Menendez-Lustri Dhariyat, Zhang Jichu, Chen Alex, Lam Danny, Traylor Baylee, Quill Emma, Hoeferlin George, Pawlowski Christa, Bruckman Michael, Gupta Sen A, Capadona Jeffrey
Case Western Reserve University.
Haima Therapeutics.
Res Sq. 2025 Feb 14:rs.3.rs-6018202. doi: 10.21203/rs.3.rs-6018202/v1.
Long-term robust intracortical microelectrode (IME) neural recording quality is negatively affected by the neuroinflammatory response following microelectrode insertion. This adversely impacts brain-machine interface (BMI) performance for patients with neurological disorders or amputations. Recent studies suggest that the leakage of blood-brain barrier (BBB) and microhemorrhage caused by the IME insertions lead to the increased neuroinflammation and reduced neural recording performance. Additionally, a sustained presence of activated platelets and coagulation factors is found near the insertion site. Thus, we hypothesized that the systemic administration of dexamethasone sodium phosphate-loaded platelet-inspired nanoparticle (SPPINDEX) can improve the neural recording performance of intracortical microelectrodes (IMEs) by promoting hemostasis, facilitating blood-brain barrier (BBB) healing, and achieving implant-targeted drug delivery. Leveraging the hemostatic and coagulation factor-binding properties of the platelet-inspired nanoparticle (PIN) drug delivery platform, SPPINDEX treatment can initially attenuate the invasion of neuroinflammatory triggers into the brain parenchyma caused by insertion-induced microhemorrhages or a compromised BBB. Furthermore, targeted delivery of the anti-inflammatory drug dexamethasone sodium phosphate (DEXSP) to the implant site via these nanoparticles can attenuate ongoing neuroinflammation, enhancing overall therapeutic efficacy. Weekly treatment with SPPINDEX for 8 weeks significantly improved the recording capabilities of IMEs compared to platelet-inspired nanoparticles alone (PIN), free dexamethasone sodium phosphate (Free DEXSP), and a diluent control trehalose buffer (TH), as assessed through extracellular single-unit recordings. Immunohistochemical analyses of neuron density, activated microglia/macrophage density, astrocyte density, and BBB permeability suggest that the improved neural recording performance may be attributed to reduced neuron degeneration, activated microglia and astrocytes at the implant interface caused by the decreased infiltration of blood-derived proteins that trigger neuroinflammation and the therapeutic effects from DEXSP. Overall, SPPINDEX treatment promotes an anti-inflammatory environment that improves neuronal density and enhances recording performance.
长期稳定的皮质内微电极（IME）神经记录质量会受到微电极插入后神经炎症反应的负面影响。这对患有神经系统疾病或截肢的患者的脑机接口（BMI）性能产生不利影响。最近的研究表明，IME插入导致的血脑屏障（BBB）渗漏和微出血会导致神经炎症增加和神经记录性能下降。此外，在插入部位附近发现有活化血小板和凝血因子持续存在。因此，我们假设全身给予负载地塞米松磷酸钠的血小板启发纳米颗粒（SPPINDEX）可以通过促进止血、促进血脑屏障（BBB）愈合以及实现植入物靶向药物递送，来改善皮质内微电极（IME）的神经记录性能。利用血小板启发纳米颗粒（PIN）药物递送平台的止血和凝血因子结合特性，SPPINDEX治疗最初可以减弱由插入引起的微出血或受损的血脑屏障导致的神经炎症触发因素侵入脑实质。此外，通过这些纳米颗粒将抗炎药物地塞米松磷酸钠（DEXSP）靶向递送至植入部位可以减弱持续的神经炎症，提高整体治疗效果。与单独的血小板启发纳米颗粒（PIN）、游离地塞米松磷酸钠（游离DEXSP）和稀释剂对照海藻糖缓冲液（TH）相比，每周用SPPINDEX治疗8周通过细胞外单单元记录评估，显著提高了IME的记录能力。对神经元密度、活化小胶质细胞/巨噬细胞密度、星形胶质细胞密度和血脑屏障通透性的免疫组织化学分析表明，神经记录性能的改善可能归因于神经元变性减少、植入界面处活化的小胶质细胞和星形胶质细胞减少，这是由于触发神经炎症的血源性蛋白质浸润减少以及DEXSP的治疗作用。总体而言，SPPINDEX治疗促进了一种抗炎环境，改善了神经元密度并提高了记录性能。
