摘要
利用种植体进行颌面赝复体的固位是目前颌面缺损修复的重要方式,已经广泛应用于眶耳、眼、鼻等多器官的缺损修复上,尤其对于颌面恶性肿瘤切除术后的患者,迫切需要进行种植体固位赝复体的重建,但是,由于术后放疗对于周围骨组织的损伤,使得种植体骨结合成功率降低,极大限制了种植体的应用。如何提高放疗区种植体骨结合的成功率一直是颌面赝复体固位研究中的“瓶颈”问题,直接关系到肿瘤术后颌面部缺损修复的质量。也有学者尝试采用高压氧治疗来提高种植体骨结合率,主要通过增加放疗组织区氧供以改善局部组织的血供,但该方法并不是在真正意义上促进种植体骨结合,更多的是起到稳定局部治疗的效果,因此目前对于高压氧是否能够促进种植体骨结合仍然存在较大的争议。
然而,随着组织工程技术的出现和发展,利用该项技术为解决种植体骨结合的问题提供了崭新的思路和方法。骨髓基质干细胞是组织工程最常用的种子细胞,具有较强的增殖和组织修复能力,我们设想通过细胞膜片技术将骨髓基质干细胞与种植体复合,体外构建具有生物活性的种植体,即组织工程化种植体,使得植入的种植体不再仅仅依靠周围组织的修复能力来获得骨结合,而是在种植体植入时其自身就具有了修复周围组织的能力并促进骨愈合。因此,本研究拟体外构建组织工程化种植体,检测其生物活性,探讨其应用于放疗区促进骨结合的可行性,以期为临床解决放疗后种植体骨结合失败率高的问题提供新的思路和方法。
所取得主要研究结果如下:
1.证实了利用组织工程技术体外构建组织工程化种植体的可行性
本实验分离培养骨髓基质干细胞并进行相关生物学检测,采用原代骨髓基质干细胞加工具有体外操作性的细胞膜片,分别与锆瓷和钛两种材料种植体复合,体外构建组织工程化种植体;通过大体观察、组织学及分子生物学技术分析其生物学特性;体内植入组织工程化种植体,研究其成骨和血管化的能力。结果显示:体外构建骨髓基质干细胞细胞膜片方法简单,细胞膜片与种植体复合后通过体外培养可以与之紧密结合,并能够继续分泌细胞外基质,成功构建组织工程化种植体;细胞、分子生物学技术检测构建的组织工程化种植体,发现其成骨和成血管相关基因和蛋白高表达。裸鼠体内移植结果证实种植体周围有血管化的骨组织生成。锆瓷和钛两种材料种植体,由于元素构成的不同,在成骨能力上钛种植体强于锆瓷种植体(P<0.05);而在促进血管生成方面,锆瓷种植体略好于钛种植体(P>0.05)。
本研究结果说明,利用骨髓基质干细胞膜片技术与种植体构建具有生物活性的组织工程化种植体,并促进种植体周围骨组织愈合的思路是可行的;不同的种植体材料成分对于组织工程化种植体的生物学特性有一定的影响。
2.不同材料种植体放疗前后植入的差异性研究
为了比较不同材料种植体,放疗前后植入对于种植体骨结合的影响,本实验选择了锆瓷和钛两种种植体材料,分别在放疗前后3个月植入,对比分析了两种种植体不同时间植入的骨结合差异。结果显示:放疗前植入种植体形成的种植体骨结合率要高于放疗后(P<0.05),钛种植体的骨结合强度要略高于锆瓷种植体(P>0.05),但是锆瓷种植体的周围组织血管化好略于钛种植体(P>0.05)。
本研究结果说明:在低于50Gy放射剂量的条件下,放疗前进行种植体植入形成的骨结合,要优于放疗后植入;钛种植体较锆瓷种植体在放疗区种植优势并不明显。
3.组织工程化种植体应用于放疗区的研究
为了评估体外构建的组织工程化种植体应用于放疗区的可行性,本实验体外抽取培养犬骨髓基质干细胞,加工成细胞膜片后,构建组织工程化种植体,植入放疗区,与常规种植体对比观察。结果显示:组织工程化种植体骨结合率要高于常规种植体(P<0.05),种植体周围骨组织愈合要优于常规种植体;锆瓷与钛两种材料构建组织工程化种植体,应用于放疗区差异不大(P>0.05)。
本研究结果说明:利用干细胞组织工程和细胞膜片技术,构建组织工程化种植体并应用于放疗区,是一种新的种植体表面处理方法的探索,为今后提高放疗区种植体骨结合率提供了新的理论和实验依据。
Until now the endosseos implants has been used for the retention of ear prosthetics, orbit prosthetics, nose prosthetics and midface prosthetics. In recent years, an increasing number of cancer patients, particularly malignant tumor patients, which urgently needed the implant-supported prosthestics after surgery. But radiotherapy, which harmed bone around implants, decreased the success rate of endosseous implant significantly and limited the application of implants. Implant failures were higher after radiotherapy, which limited the use of endosseous implant supported maxillofacial prosthetics. How to resolve this "bottleneck" problem directly related to the retension effect of maxillofacial prosthetics. The therapeutic effect of HBO is related to an elevated partial pressure of oxygen in the tissue. The pressure itself enhances oxygen solubility in the tissue fluids. HBO only plays an adjunctive roles as only stationary results are achieved local reatement. Whether HBO improve the osseointegration is still controversy.
In resent years, however, the devolpment of tissue engineering technology may provide a new way to solve the osseointegration problem. Bone marrow stem cells (MSCs) with strong proliferation and tissue repair are the most commonly used in tissue engineering as seed cells. The MSC-implant composed by MSC cell sheet with implants in vitro forms the osseointegration not only by bone tissue around implant, but also by MSCs aound implant. Then we hypothesize that MSC-implant have the ability to accelerate the implant ossintegration in irradiated bone. Therefore, this study was to construct MSC-implant in vitro, to test its biology and explore the feasibility to use in irradiated bone, in order to provide a new way to resolve the implant failure problem.
The major findings are as follows:
Part I. Confirmed feasibility of construction Msc-implant in vitro with tissue engineering technology
In this study, we isolated and cultured bone marrow-derived mesenchymal stem cells (MSCs) and formed the cell sheet, then constructed the MSC-implant with two kinds of implant in vitro. The biological properties of MSC-implant were analyzied in gross, histological, and molecular level. After thransplanted in nude mouse, the MSC-implant can regenerate bone-like tissue and vascular-like tissue. The results showed that bone marrow mesenchymal stem cells formed cell sheet easily which could composed with implant tightly in vitro. The MSCs in cell sheet still kept secreting extracellular matrix. The novel MSC-implant had the ability to form new bone and blood vessels, and expressed the osteogenesis and vascular gene. The Ti implant had higher capability to accelerate the bone forming than Zr implant. But it was lower in accelerating the vascular forming.
The results suggest that it is feasibility to construct the MSC-implant in vitro, which has the ability to accelerate the tissue healing. The different materials of implants have the different impact on cell sheet.
Part II: the study of different implants inserting the irradiated bone in different time
In order to compare different materials implants insertion before and after radiotherapy had the impact on osseointegration. Two kinds of zirconia ceramic and titanium implant were selected. The study compared the different osseointegration before and after 3 months irradiation. The results showed that: bone-implant contact (BIC) was higher before irradiation insertion implants than after irradiation. The osseointegrated strength of titanium implants was higher than zirconia implants, while in vascular forming it was lower.
The results suggest that the ossointegration insertion before irradiation, less than 50Gy radiation dose, was significantly better than after irradiation insertion. There was no obvious difference between titanium and zirconia implants used in irradiated bone.
Part III: the study about MSC-implants used in irradiated bone
To assess the effect of MSC-implant, which was constructed in vitro,, inserted in irradiated bone. The MSCs of dogs were isolated and cultured, formed the cell sheet and constructed the MSC-implant. Then it was inserted in irradiated bone compared with normal implants. The results showed that the MSC-implant had higher capability to accelerate bone healing than normal implants. There were no obvious different between MSC-Ti implant and MSC-Zr implant when they inserted in irradiated bone.
The results suggests that contructing MSC-implant in vitro inserts in irradiated bone may be a novel implant surface modifying method, which could improve the success rate of implants in irradiated bone.
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