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Are Developments in Biomaterials Science converging fast enough with Additive Manufacturing and Biofabrication technologies for Translational Regenerative Medicine?

机译:生物材料科学的发展是否与转化转化医学的增材制造和生物制造技术融合得足够快?

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Additive Manufacturing (AM) has opened new frontiers in medicine and enabled the use of patient-specific design in medical device manufacturing. In combination with medical imaging, AM allows the direct layer-by-layer fabrication of implants consisting of fully dense and/or porous tissue-ingrowth surfaces with most orthopaedic devices fabricated from titanium and more recently polymers (e.g. PEEK). In this era of personalized medicine, AM has made particular impact in development of custom titanium implants for complex revision surgery requiring large bone void filling. Despite AM technologies such as electron beam melting (EBM) and selective laser melting (SLM) being available for almost a decade, few studies have evaluated the long term clinical performance of AM orthopaedic devices. We highlight clinical experience of AM implants for complex acetabular revision surgery where patient-specific shape and optimisation of porous titanium mesh design allow successful large bone void filling at 2year follow-up, offering cost savings demonstrated through both faster surgery time and patient recovery. Further converging developments in biomaterials science, particularly in AM of degradable metals such as magnesium and hybrid technologies will also be discussed. In the long-term, however, the 'holy grail' in future orthopaedic surgery is widely accepted as the successful implementation of strategies that regenerate rather than replace damaged or diseased joint tissues such as bone and cartilage. Advances in biofabrication technologies, including 3D bio-printing and bio-assembly, enable the generation of engineered constructs that replicate the complex organization of native tissues via the automated placement of cell-laden bio-inks, tissue modules, growth factors and/or bioactive agents for Regenerative Medicine, or eventually functional 'biological' joint replacement. Advanced AM and biofabrication technologies are well established. The greatest challenge in successful bio-printing of living tissues for translational regenerative medicine is not in hardware development but in the convergence of biomaterials science to develop improved biomaterials and bio-inks. In this regard, hydrogels are commonly investigated as bio-inks for biofabrication as they provide a hydrated 3D environment for cell encapsulation that mimic features of native extracellular matrix including growth factor binding, adhesion and degradability. For successful bio-printing of high fidelity constructs, an ideal bio-ink should rapidly undergo transitions in viscosity from a state of flow during extrusion to a full gelation state once printed. Furthermore, the bio-ink material and especially the process for crosslinking must be biocompatible and cell friendly. For these reasons gelatin-based bio-inks (e.g. gelatin methacryloyl, gelMA) have been most commonly reported, and when combined with a photo-initiator (lrgacure®2959) gelMA bio-inks can be crosslinked under UV light via radical polymerization'6!, this approach in itself presents major challenges to clinical translation: 1) additional rheology modifying agents (e.g. gellan gum, collagen) are necessary to achieve high fidelity constructs; 2) UV radiation causes photo-toxicity and reduced cell viability; 3) UV crosslinking performed in the presence of oxygen to maintain cell survival and viability interferes with radical polymerization causing 'oxygen inhibition' and incomplete crosslinking, which in turn leads to undesirable loss of print fidelity. We describe development of alternative gelMA hydrogels usingnovel s visible light initiators (400-450nm) that significantly reduce oxygen inhibition and increase cell survival and metabolic activity. We also report on a new synthetic 'bio-resin' based on methacrylated poly(vinyl alcohol) (PVA-MA) for cell encapsulation using light projection stereolithography as alternative approaches to achieve high print resolution for biofabrication of blood vessels or complex 3D tissues. These hydrogel 'bio-inks' and 'bio-resins' - while stable after crosslinking - are all intrinsically weak and suffer from low mechanical properties. New hybrid strategies will be discussed which combine 3D printing or melt-electrospinning to fabricate organized reinforcing polymer networks for embedding within biofabricated hydrogel bioinks resulting in significant increases in mechanical strength of these hybrid constructs. Furthermore, alternative bottom-up or modular approaches for high throughout fabrication of cellular microtissues or spheroids for automated bio-assembly into 3D printed reinforced polymer scaffolds are introduced. These approaches promote high density cell-cell interactions that mimic stages of developmental growth and tissue formation while allowing biofabrication of complex constructs containing pre-differentiated microtissues with mechanical properties replicating those of native tissues.
机译:增材制造(AM)在医学领域开辟了新的领域,并允许在医疗设备制造中使用针对患者的设计。结合医学成像,AM可以直接逐层制造由完全致密和/或多孔的组织向内生长表面组成的植入物,而大多数骨科器械均由钛和最近的聚合物(例如PEEK)制成。在这个个性化医学的时代,AM在用于需要大量骨空隙填充的复杂翻修手术的定制钛植入物的开发中产生了特别的影响。尽管AM技术(例如电子束熔化(EBM)和选择性激光熔化(SLM))可用了将近十年,但很少有研究评估AM矫形设备的长期临床性能。我们着重介绍了用于复杂髋臼翻修手术的AM植入物的临床经验,其中患者特定的形状和多孔钛网设计的优化可确保在2年的随访中成功地成功填充大的骨腔,从而通过缩短手术时间和患者康复证明了成本节省。也将讨论生物材料科学的进一步融合发展,特别是可降解金属(例如镁)和混合技术在增材制造方面的发展。但是,从长远来看,未来骨科手术中的“圣杯”被公认为成功实施了再生策略,而不是替代受损或患病的关节组织(如骨骼和软骨)。生物制造技术的进步,包括3D生物打印和生物组装,使得能够生成工程化的构建体,从而通过载有细胞的生物墨水,组织模块,生长因子和/或生物活性物质的自动放置来复制天然组织的复杂组织。再生医学或最终的功能性“生物”关节置换药物。先进的增材制造和生物制造技术已经建立。成功地将生物组织进行转化再生医学生物打印的最大挑战不是硬件开发,而是生物材料科学的融合以开发改进的生物材料和生物墨水。在这方面,水凝胶通常被研究为生物制造用生物墨水,因为它们为细胞包封提供了水合的3D环境,可模仿天然细胞外基质的特征,包括生长因子结合,粘附和降解性。为了成功地对高保真结构进行生物印刷,理想的生物油墨应迅速经历粘度的变化,从挤出过程中的流动状态到印刷后的完全胶凝状态。此外,生物墨水材料,尤其是交联过程必须是生物相容的且对细胞友好的。由于这些原因,最常报道的是基于明胶的生物油墨(例如,明胶甲基丙烯酰,gelMA),当与光引发剂(lrgacure®2959)组合使用时,gelMA生物油墨可以在紫外线下通过自由基聚合而交联'6 ,这种方法本身给临床翻译带来了重大挑战:1)为了获得高保真度的构建体,还需要其他流变改性剂(例如结冷胶,胶原蛋白); 2)紫外线会引起光毒性并降低细胞活力; 3)在氧气存在下进行的UV交联可维持细胞存活和生存力,从而干扰自由基聚合,导致“氧气抑制”和不完全交联,进而导致印刷保真度下降。我们描述了使用novel的可见光引发剂(400-450nm)替代凝胶MA水凝胶的开发,该凝胶显着降低了氧的抑制作用并增加了细胞存活率和代谢活性。我们还报告了一种基于甲基丙烯酸酯化的聚乙烯醇(PVA-MA)的新型合成“生物树脂”,用于使用光投射立体光刻技术作为细胞封装的细胞封装技术,以实现用于血管或复杂3D组织生物制造的高打印分辨率。这些水凝胶的“生物油墨”和“生物树脂”虽然在交联后稳定,但本质上都很弱并且具有较低的机械性能。将讨论将3D打印或熔融静电纺丝结合在一起以制造有组织的增强聚合物网络,以嵌入到生物制造的水凝胶生物油墨中的新混合策略,从而显着提高这些混合结构的机械强度。此外,介绍了用于自下而上或模块化的方法,用于从头到尾地制造细胞微组织或球体,以将生物自动组装到3D打印的增强型聚合物支架中。这些方法促进了高密度细胞-细胞相互作用,该相互作用模拟了发育生长和组织形成的阶段,同时允许生物制造包含预分化的微组织的复杂构建体,而这些复制体的机械性能可复制天然组织的机械性能。

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