Bone regeneration of large cranial defects, potentially including traumatic brain injury (TBI) treatment, presents a major problem with non-crosslinking, clinically available products due to material migration outside the defect. Commercial products such as bone cements are permanent and thus not conducive to bone regeneration, and typical commercial bioactive materials for bone regeneration do not crosslink. Our previous work demonstrated that non-crosslinking materials may be prone to material migration following surgical placement, and the current study attempted to address these problems by introducing a new hydrogel system where tissue particles are themselves the crosslinker. Specifically, a pentenoate-modified hyaluronic acid (PHA) polymer was covalently linked to thiolated tissue particles of demineralized bone matrix (TDBM) or devitalized tendon (TDVT), thereby forming an interconnected hydrogel matrix for calvarial bone regeneration. All hydrogel precursor solutions exhibited sufficient yield stress for surgical placement and an adequate compressive modulus post-crosslinking. Critical-size calvarial defects were filled with a 4% PHA hydrogel containing 10 or 20% TDBM or TDVT, with the clinical product DBXⓇ being employed as the standard of care control for the in vivo study. At 12 weeks, micro-computed tomography analysis demonstrated similar bone regeneration among the experimental groups, TDBM and TDVT, and the standard of care control DBXⓇ. The group with 10% TDBM was therefore identified as an attractive material for potential calvarial defect repair, as it additionally exhibited a sufficient initial recovery after shearing (i.e., > 80% recovery). Future studies will focus on applying a hydrogel in a rat model for treatment of TBI. STATEMENT OF SIGNIFICANCE: Non-crosslinking materials may be prone to material migration from a calvarial bone defect following surgical placement, which is problematic for materials intended for bone regeneration. Unfortunately, typical crosslinking materials such as bone cements are permanent and thus not conducive to bone regeneration, and typical bioactive materials for bone regeneration such as tissue matrix are not crosslinked in commercial products. The current study addressed these problems by introducing a new biomaterial where tissue particles are themselves the crosslinker in a hydrogel system. The current study successfully demonstrated a new material based on pentenoate-modified hyaluronic acid with thiolated demineralized bone matrix that is capable of rapid crosslinking, with desirable paste-like rheology of the precursor material for surgical placement, and with bone regeneration comparable to a commercially available standard-of-care product. Such a material may hold promise for a single-surgery treatment of severe traumatic brain injury (TBI) following hemicraniectomy.

中文翻译：

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硫醇化的骨和腱组织颗粒共价结合在水凝胶中，用于体内颅骨的再生。

大颅骨缺损的骨再生，可能包括创伤性脑损伤（TBI）治疗，由于材料向缺损部位的迁移而成为非交联的临床可用产品的主要问题。商业产品（例如骨水泥）是永久性的，因此不利于骨再生，并且用于骨再生的典型商业生物活性材料不会交联。我们以前的工作表明，非交联材料在手术放置后可能易于发生材料迁移，当前的研究试图通过引入一种新的水凝胶系统来解决这些问题，其中组织颗粒本身就是交联剂。特别，将戊烯酸酯改性的透明质酸（PHA）聚合物与脱矿质骨基质（TDBM）或失活肌腱（TDVT）的硫醇化组织颗粒共价连接，从而形成互连的水凝胶基质，用于颅骨再生。所有水凝胶前体溶液均显示出足够的屈服应力以进行外科手术放置，并具有足够的交联后的压缩模量。临界大小的颅骨缺损用含10％或20％TDBM或TDVT的4％PHA水凝胶填充，临床产品DBXⓇ被用作体内研究的护理控制标准。在第12周时，微型计算机断层扫描分析显示实验组TDBM和TDVT以及护理控制标准DBXⓇ中的骨再生相似。因此，将TDBM含量为10％的组确定为潜在的颅骨缺损修复的有吸引力的材料，因为它在剪切后还表现出足够的初始恢复（即> 80％的恢复率）。未来的研究将集中于在大鼠模型中应用水凝胶治疗TBI。重要性声明：非交联材料在手术放置后可能易于从颅骨缺损处迁移，这对于用于骨再生的材料而言是有问题的。不幸的是，典型的交联材料例如骨水泥是永久性的，因此不利于骨再生，并且用于骨再生的典型生物活性材料例如组织基质在商业产品中没有交联。当前的研究通过引入一种新的生物材料解决了这些问题，其中组织颗粒本身就是水凝胶系统中的交联剂。当前的研究成功地证明了一种新材料，该材料基于戊烯酸酯改性的透明质酸和硫醇盐化的去矿质骨基质，能够快速交联，具有用于外科手术放置的前体材料所需的糊状流变性能，并且具有与市售可比的骨再生护理标准产品。这种材料有望为半颅脑切除术后单次手术治疗严重的颅脑外伤（TBI）。当前的研究成功地证明了一种新材料，该材料基于戊烯酸酯改性的透明质酸和硫醇盐化的去矿质骨基质，能够快速交联，具有用于外科手术放置的前体材料所需的糊状流变性能，并且具有与市售可比的骨再生能力护理标准产品。这种材料有望为半颅脑切除术后单次手术治疗严重的颅脑外伤（TBI）。当前的研究成功地证明了一种新材料，该材料基于戊烯酸酯改性的透明质酸和硫醇盐化的去矿质骨基质，能够快速交联，具有用于外科手术放置的前体材料所需的糊状流变性能，并且具有与市售可比的骨再生能力护理标准产品。这种材料有望为半颅脑切除术后单次手术治疗严重的颅脑外伤（TBI）。