临床上存在对替代新鲜骨移植物的替代物以治疗由外伤或疾病引起的骨缺损的重要临床需求。自体骨移植物是骨再生的金标准，因为它们缺乏异体和异种组织中存在的复杂免疫因子，并且具有对骨再生重要的三个特性：骨诱导性，骨传导性和成骨性。不幸的是，自体移植的采集过程会导致供体部位发病，并且采集手术的高度侵入性会带来可能的并发症，例如增加感染风险。同种异体骨和异种异体骨移植与自体移植没有相同的供体部位发病率问题。然而，与自体移植相比，两者都引起免疫原性问题，并且生物学性能受到损害。

模块化组织工程学的新兴领域集中于通过“自下而上”的组装方法从微观结构构建整个宏观组织。模块化组织工程提供了模仿天然组织的微体系结构特征，控制整个构建体中细胞密度并消除质量运输限制的可能性，因为可以在细胞增殖/基质沉积后将微尺度构建体单独培养并融合成更大的构建体。微观构建块可以由骨细胞外基质的生理成分形成。磷酸钙陶瓷的能力，例如羟基磷灰石（HAP），以增强骨祖细胞的成骨作用已被充分证明。此外，先前的研究表明，硫酸软骨素4（C4S）在骨骼愈合过程中促进成骨细胞分化，并通过钙离子螯合支持矿化作用。可以将这种骨传导/骨诱导材料与骨再生细胞结合以形成用于模块化骨组织工程策略的微型构建体。

近日，韦恩州立大学化学工程与材料科学系的Howard William TrevorMatthew团队建立一种先前的细胞包封策略，该策略有助于将各种哺乳动物细胞封装在中空微囊中，并具有由壳聚糖和糖胺聚糖（GAG）组成的微囊膜。先前的研究表明，C4S和壳聚糖均可使MSC分化为成骨细胞系，而壳聚糖/ C4S复合材料可被表达碱性磷酸酶（ALP）的细胞矿化。该系统具有固有的可扩展性，因为可以通过向更大的模具中添加更多的微胶囊来创建更大的融合结构。可以通过将一种聚合物空气挤出到另一种聚合物中来轻松制造微胶囊，并且可以对该工艺进行修改以制造更大批次的微胶囊，从而促进将台式组织工程设计转化为最终的临床产品。或者，矿化的微胶囊可形成可注射或3D生物打印部署策略的基础。

A significant clinical need exists for alternatives to fresh bone grafts to treat bone defects caused by trauma or disease . Autologous bone grafts are the gold standard for bone regeneration because they lack the complicating immune factors present in allogenic and xenogeneic tissue, and contain the three properties important for bone regeneration: osteoinductivity, osteoconductivity, and osteogenicity . Unfortunately, the autograft harvesting procedure causes donor-site morbidity, and the highly invasive nature of the harvesting surgery introduces possible complications, such as increased risk of infection. Allogenic and xenogenic bone grafts do not pose the same donor-site morbidity issues as autografts; however, both pose immunogenicity concerns, and have compromised biological performance compared to autografts .

 

The emerging field of modular tissue engineering focuses on fabricating whole macro-scale tissues from micro-scale constructs via a “bottom-up” assembly approach . Modular tissue engineering offers the possibility of mimicking native tissue’s microarchitectural features, controlling cell density throughout a construct, and eliminating mass transport limitations, as the micro-scale constructs can be cultured individually and fused into a larger construct after cell proliferation/matrix deposition . The micro-scale building blocks could be fashioned from physiological components of bone extracellular matrix. The ability of calcium phosphate ceramics, such as hydroxyapatite (HAP), to enhance osteogenesis of bone progenitors is well documented . Additionally, previous research demonstrated that chondroitin 4-sulfate (C4S) promotes osteoblast differentiation during bone healing, and supports mineralization via calcium ion sequestration . Such osteoconductive/osteoinductive materials could be combined with bone regenerating cells to form micro-scale constructs for a modular bone tissue engineering strategy.

Recently, Professor Howard William TrevorMatthew from Department of Chemical Engineering and Materials Science builded off a previous cell encapsulation strategy that facilitated the encapsulation of various mammalian cells in hollow microcapsules, with a microcapsule membrane composed of chitosan and glycosaminoglycans (GAGs) . Previous studies showed that both C4S and chitosan allow MSC differentiation to an osteogenic lineage , and chitosan/C4S composites can be mineralized by cells expressing alkaline phosphatase (ALP) . The system is inherently scalable, as larger fused constructs can be created with the addition of more microcapsules to a larger mold. The microcapsules are easily fabricated by air extrusion of one polymer into another, and the process can be modified to manufacture larger batches of microcapsules, facilitating the translation of bench tissue engineering designs to eventual clinical products. Alternatively, the mineralized microcapsules could form the basis of injectable or 3D bioprinting deployment strategies.

DOI:10.1016/j.actbio.2019.01.04.

吴硕