Department of Orthopaedics, University Medical Center Utrecht, Heidelberglaan 100, 3584CX Utrecht, the Netherlands; Regenerative Medicine Utrecht, Utrecht University, Uppsalalaan 8, 3584CT Utrecht, the Netherlands; SentryX B.V., Woudenbergseweg 41, 3711 AA Austerlitz, the Netherlands.
Department of Orthopaedics, University Medical Center Utrecht, Heidelberglaan 100, 3584CX Utrecht, the Netherlands; SentryX B.V., Woudenbergseweg 41, 3711 AA Austerlitz, the Netherlands.
Acta Biomater. 2022 Jul 1;146:145-158. doi: 10.1016/j.actbio.2022.05.007. Epub 2022 May 11.
Adequate treatment of pain arising from spinal surgery is a major clinical challenge. Opioids are the mainstay of current treatment methods, but the frequency and severity of their side effects display a clear need for opioid-free analgesia. Local anesthetics have been encapsulated into sustained-release drug delivery systems to provide postoperative pain relief. However, these formulations are limited by rapid diffusion out of the surgical site. To overcome this limitation, we synthesized ring-shaped hydrogels incorporating bupivacaine, designed to be co-implanted with pedicle screws during spinal surgery. Hydrogels were prepared by riboflavin-mediated crosslinking of gelatin functionalized with tyramine moieties. Additionally, oxidized β-cyclodextrin was introduced into the hydrogel formulation to form dynamic bonds with tyramine functionalities, which enables self-healing behavior and resistance to shear. Feasibility of hydrogel implantation combined with pedicle screws was qualitatively assessed in cadaveric sheep as a model for instrumented spinal surgery. The in-situ crystallization of bupivacaine within the hydrogel matrix provided a moderate burst decrease and sustained release that exceeded 72 hours in vitro. The use of bupivacaine crystals decreased drug-induced cytotoxicity in vitro compared to bupivacaine HCl. Thus, the presented robust hydrogel formulation provides promising properties to enable the stationary release of non-opioid analgesics following spinal surgery. STATEMENT OF SIGNIFICANCE: Currently, postoperative pain following spinal surgery is mainly treated with opioids. However, the use of opioids is associated with several side effects including addiction. Here we developed robust and cytocompatible gelatin hydrogels, prepared via riboflavin-mediated photocrosslinking, that can withstand orthopedic implantation. The implantability was confirmed in cadaveric instrumented spinal surgery. Further, hydrogels were loaded with bupivacaine crystals to provide sustained release beyond 72 hours in vitro. The use of crystallized bupivacaine decreased cytotoxicity compared to bupivacaine HCl. The present formulation can aid in enabling opioid-free analgesia following instrumented spinal surgery.
脊柱手术后疼痛的充分治疗是一个主要的临床挑战。阿片类药物是当前治疗方法的主要手段，但它们的副作用频率和严重程度表明，需要无阿片类药物的镇痛。局部麻醉剂已被包裹在持续释放的药物输送系统中，以提供术后疼痛缓解。然而，这些制剂受到从手术部位迅速扩散的限制。为了克服这一限制，我们合成了包埋布比卡因的环形水凝胶，设计用于在脊柱手术期间与椎弓根螺钉一起植入。水凝胶通过含有酪胺部分的明胶的核黄素介导的交联制备。此外，氧化的β-环糊精被引入水凝胶配方中，与酪胺官能团形成动态键，从而实现自修复行为和抗剪切。作为有创脊柱手术模型的尸体羊体内，定性评估了与椎弓根螺钉联合植入水凝胶的可行性。布比卡因在水凝胶基质中的原位结晶提供了适度的爆发性降低和持续释放，在体外超过 72 小时。与布比卡因 HCl 相比，布比卡因晶体的使用降低了体外的药物诱导细胞毒性。因此，所提出的稳健水凝胶配方提供了有前途的特性，可实现脊柱手术后非阿片类镇痛药的固定释放。
目前，脊柱手术后的术后疼痛主要用阿片类药物治疗。然而，阿片类药物的使用与包括成瘾在内的多种副作用相关。在这里，我们开发了稳健且细胞相容的明胶水凝胶，通过核黄素介导的光交联制备，可承受矫形植入物。在尸体有创脊柱手术中证实了可植入性。此外，水凝胶负载布比卡因晶体，可提供超过 72 小时的体外持续释放。与布比卡因 HCl 相比，结晶布比卡因的使用降低了细胞毒性。本配方可帮助实现有创脊柱手术后的无阿片类药物镇痛。
