Jingyao Deng^1,*; David Cohen¹; Zvi Schwartz^1,2; Barbara Boyan^1,3

¹Biomedical Engineering, Virginia Commonwealth University, Richmond; ²Periodontics, University of Texas Health Science Center at San Antonio, San Antonio; ³Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, United States

Background: Successful osseointegration of titanium implants in type 2 diabetic (T2DM) patients remains a challenge. Current T2DM rodent models lack translatability to human conditions. This project used a more clinically related T2DM rat model that had natural T2DM progression as in humans. Semaphorin 3A (sema3A) is a novel osteoprotective factor that has been reported to increase bone formation, suggesting that it may have applicability in supporting osteogenesis and improving osseointegration.

Aim/Hypothesis: This study established the use of Zucker Diabetic Sprague Dawley rats as a T2DM model for examining the osseointegration success against wild animals and investigated the ability of sema3A to recover the osseointegration in this clinically translatable T2DM model.

Material and Methods: 30 male 15-week-old Zucker Diabetic Sprague Dawley rats (D) and 24 aged-matched male Sprague Dawley rats (N) were used. The D rats were fed a high-fat diet until 70% of them became diabetic and switched to a normal diet. Three weeks after turning diabetic, D rats were randomized to three groups: click hydrogel delivery vehicle (D GEL), hydrogel containing 3A (D 3A+GEL), hydrogel implanted, and 3A injected separately (D i3A+GEL) with n = 7. N rats were randomized to N GEL, N 3A+GEL, N i3A+GEL with n = 8. Hydrogels were formed in the hole by mixing PEG-N3 and PEG-DBCO crosslinker with either 0.9% sterile saline in GEL and i3A+GEL or with 6μg 3A in 3A+GEL. Microrough/hydrophobic grit blasted/acid etched (SLA) titanium implants (Institut Straumann AG) were inserted after gelation. i3A+GEL had bilateral subperiosteal 3A injections (6μg/leg) at implant sites on day 3 and day 10 post-surgery. Osseointegration was evaluated by microCT, histology, and removal torque test 4 weeks post-surgery.

Results: MicroCT showed that diabetic rats had less trabecular bone formation than normal rats with less BV/TV, and higher total porosity. Cortical bones were not affected by diabetes. Diabetes reduced total bone to implant contact (BIC), bone marrow BIC, and cortical BIC. Sema3A had no effect on the lowered total BIC, but sema3A delivered by hydrogel increased bone marrow BIC and eliminated the diabetic-normal difference. Sema3A local injection also overrode the cortical BIC difference. Furthermore, histology confirmed the diabetic effect on inhibiting BIC and showed that sema3A improved total and cortical BIC and overrode the diabetic-normal discrepancy. Bone marrow BIC was only recovered when sema3A was delivered by the hydrogel. Torsional stiffness was less in diabetes, but sema3A increased it and counteracted the diminished torsional stiffness in diabetic rats. There was no significant difference in maximum torque among all groups.

Conclusion and Clinical implications: Reduced osseointegration was found in the clinically translatable T2DM model. Sema3A counteracted the inhibited osseointegration in T2DM compromised conditions, which suggests its therapeutic potential role in enhancing osseointegration in type 2 diabetic patients.

Disclosure of Interest: J. Deng: None Declared, D. Cohen: None Declared, Z. Schwartz Conflict with: AB Dental, B. Boyan Conflict with: Institut Straumann AG

Keywords: biomaterial, osseointegration, titanium

邓敬尧^1,* ; 大卫科恩¹ ; 兹维施瓦茨^1,2 ; 芭芭拉·博扬^1,3

¹生物医学工程，弗吉尼亚联邦大学，里士满；²牙周病学，德克萨斯大学圣安东尼奥健康科学中心，圣安东尼奥；³ Wallace H. Coulter 美国亚特兰大佐治亚理工学院生物医学工程系

背景：钛种植体在 2 型糖尿病 (T2DM) 患者中的成功骨整合仍然是一个挑战。当前的 T2DM 啮齿动物模型缺乏对人类条件的可译性。该项目使用了更具有临床相关性的 T2DM 大鼠模型，该模型具有与人类一样的自然 T2DM 进展。Semaphorin 3A (sema3A) 是一种新型骨保护因子，据报道可增加骨形成，表明它可能适用于支持成骨和改善骨整合。

目的/假设：本研究建立了 Zucker 糖尿病 Sprague Dawley 大鼠作为 T2DM 模型的用途，用于检查针对野生动物的骨整合成功，并研究了 sema3A 在该临床可转化的 T2DM 模型中恢复骨整合的能力。

材料和方法：使用30 只 15 周龄雄性 Zucker 糖尿病 Sprague Dawley 大鼠（D）和 24 只同龄雄性 Sprague Dawley 大鼠（N）。D 大鼠被喂食高脂肪饮食，直到其中 70% 变成糖尿病并转为正常饮食。转为糖尿病三周后，D 大鼠随机分为三组：点击水凝胶递送载体（D GEL）、含有 3A 的水凝胶（D 3A+GEL）、植入的水凝胶和单独注射 3A（D i3A+GEL），n = 7 . N 只大鼠被随机分配到 N GEL、N 3A+GEL、N i3A+GEL 和n= 8. 通过将 PEG-N3 和 PEG-DBCO 交联剂与 GEL 和 i3A+GEL 中的 0.9% 无菌盐水或 3A+GEL 中的 6μg 3A 混合，在孔中形成水凝胶。凝胶化后插入微粗糙/疏水喷砂/酸蚀刻 (SLA) 钛植入物 (Institut Straumann AG)。i3A+GEL 在术后第 3 天和第 10 天在植入部位进行双侧骨膜下 3A 注射（6μg/腿）。手术后 4 周通过显微 CT、组织学和移除扭矩测试评估骨整合。

结果：MicroCT 显示，与正常大鼠相比，糖尿病大鼠的骨小梁形成较少，BV/TV 较少，总孔隙率较高。皮质骨不受糖尿病影响。糖尿病减少了总骨与植入物接触 (BIC)、骨髓 BIC 和皮质 BIC。Sema3A 对降低的总 BIC 没有影响，但由水凝胶递送的 sema3A 增加了骨髓 BIC 并消除了糖尿病-正常差异。Sema3A 局部注射也覆盖了皮质 BIC 差异。此外，组织学证实了糖尿病对抑制 BIC 的作用，并表明 sema3A 改善了总 BIC 和皮质 BIC，并克服了糖尿病与正常的差异。仅当 sema3A 由水凝胶递送时，骨髓 BIC 才会恢复。糖尿病患者的扭转刚度较小，但 sema3A 增加了它并抵消了糖尿病大鼠扭转刚度的降低。所有组之间的最大扭矩没有显着差异。

结论和临床意义：在临床可转化的 T2DM 模型中发现骨整合减少。Sema3A 抵消了 T2DM 受损条件下受抑制的骨整合，这表明其在增强 2 型糖尿病患者的骨整合方面的潜在治疗作用。

利益披露：J. Deng：未声明，D. Cohen：未声明，Z. Schwartz 与：AB Dental、B. Boyan 的冲突与：Institut Straumann AG

关键词: 生物材料, 骨整合, 钛