1 Introduction

Nanocellulose (NC) is a kind of cellulose whose specific size is in the nanometer range, including bacterial cellulose (BC), nanocrystalline cellulose (NCC), and nanofibrillated cellulose (NFC)[1]. Among these, NCC is also known as cellulose nanocrystal (CNC) or cellulose nanowhisker (CNW), while NFC is also known as cellulose nanofibers (CNF). In addition, the nano-sized cellulose fibers prepared by electrospinning from cellulose and its derivatives, such as cellulose acetate (CA)and carboxymethyl cellulose (CMC), are defined herein as electrospun cellulose nanofibers (ESC). Since ESC is nanostructured, it is also classified as NC. Different from the macro-sized cellulose, NC generally combines several properties, including a high specific surface area, high mechanical strength, and light weight. NC also maintains the excellent characteristics of traditional cellulosic materials, which can be regenerated and is widely sourced and degradable. Therefore, the NC family exhibits appealing prospects for a wide range of applications, including drug delivery, food,biosensors, and tissue Engineering (TE)[2-5].

将城市绿化工作正式纳入法制管理中的是在1992年5月通过的《城市绿化条例》，它是新中国成立以来第一个有关城市绿化的法规。同年，建设部发布了CJJ 48—1992《公园设计规范》，确保公园能够全面发挥游憩和改善环境的功能，同年又开展了“创建‘园林城市’”的工作，以此带动各地风景园林建设水平的提升。1995年，建设部印发了《城市园林绿化企业资质管理办法》和《城市园林绿化企业资质标准》，将园林绿化企业从建工企业中分离以来，各地相关部门也开始城市园林立法工作，地方性行政法规与行业规范进入完善期。

TE is a special technology for repairing and reconstructing lesions by seeding cells onto scaffold materials under the regulation of growth factors to construct functional tissues or organs in vitro or in vivo[6]. It is expected to overcome the limits of clinical autologous tissue and organ shortage as well as immune rejection during transplantation[7]. TE involves a large scale of applications, which covers the repair and reconstruction of almost all body tissues including hard tissue and soft tissue, just like a “body parts factory”.

As a kind of biomass material, NC is biocompatible,non-toxic, and harmless, because of which its applications in TE scaffolds have drawn great interest in recent years. There are many hydroxyl groups in the structure of NC, and thus, intra-chain and interchain hydrogen bonds can easily form with orderly arrangement, thereby constituting a highly regular crystalline structure of NC, leading to a high mechanical strength, good water absorption and retention, and strong interaction with living cells, which endow bright prospects in TE technology[8-11]. In particular,when applied in hard TE, the scaffold materials usually require higher mechanical strength than that required in soft TE. Hence, the requirements for mechanical properties make NC the best choice for the preparation and reinforcement of TE scaffolds. The classification of NC and its applications in hard TE are shown in Fig.1.

In this review, we mainly described the applications of NC in hard TE represented by cartilage TE, bone TE, and dental TE. We also summarized the different processing methods for the preparation of scaffolds,and finally presented future perspectives on NC-based scaffold composites.

2 Applications of NC in hard TE

There are many other processing methods in bone TE technology to satisfy the requirements of different scaffolds. For instance, by employing the solvent casting/particulate leaching process, polyurethane/NCC bimodal foam nanocomposites were synthesized for osteogenic differentiation of hMSCs[53]. The incorporation of different NCCs led to the generation of tunable mechanical properties and biodegradable structures, and the elastic modulus and tensile strength of the highly porous composites increased significantly with the addition of NCC. All these nanocomposites were biodegradable and non-cytotoxic. Moreover,these researchers also extracted NCC from waste paper by acid hydrolysis and calcification, and prepared phosphorized calcified cellulose nanowhiskers(PCCNW), which were found to have positive effects on the osteogenic differentiation of hMSCs; thus,they showed promising prospects in the development of new bone TE technologies[30]. In addition, a study on alginate-gelatin-NCC injectable hydrogels was conducted, which intended to provide an environment for cell growth and proliferation, facilitate the exchange of nutrients, and achieve the mechanical properties that resemble natural tissues[54]. NCC affected the degradation and interaction between hydrogels and cells prominently, and enhanced the mechanical properties.The hydrogel possessed the required mechanical properties and was biocompatible, and therefore might be applied in bone regeneration.

On the other hand, NC is composed of cellulose molecular chains with a large number of hydroxyl groups, and therefore, a hydrogen bonding network can be easily formed[9, 13]. Thus, NC has crystal characteristics and prominent mechanical properties,which are obvious advantages that enhance the composites. For example, a highly regulatable and injectable poly(oligoethylene glycol methacrylate)-based hydrogel (POEGMA-based hydrogel) was developed, and the rigid rod-shaped NCCs were physically bound to the hydrazone-crosslinked POEGMA-based hydrogel[14]. The strong adsorption of hydrazide and aldehyde-modified POEGMA precursor polymers on the surface of NCC contributed to the uniform dispersion of NCC and increased the overall mechanical strength significantly. The addition of as low as 5 wt% NCC could drastically increase the mechanical properties especially the storage modulus. In another research, electrospun nanofiber mats based on PLA-g-silane/NCC and PLA/NCC nanocomposites were synthesized and immersed in hot water (70℃) to crosslink the silane-grafted PLA[15]. The influence of NCC on the tensile strength was prominent, and the mechanical properties of the nanofibers were significantly improved by chemical crosslinking.

2.1 Cartilage TE

As a novel processing method, 3D printing stands out in the TE technology with many advantages such as flexibility, high efficiency, and accuracy. The bioink properties such as good printability and cell viability,are the key to the application of 3D printing, which has attracted great attention[20-22].

2.4 两组不良反应比较 治疗过程中，两组均未出现红细胞减少、血小板下降，对照组出现白细胞减少1例（2.08%）、恶心1例（2.08%）、头晕1例（2.08%），不良反应发生率为6.25%；研究组出现白细胞减少2例（4.17%）、恶心1例（2.08%）、皮疹1例（2.08%），不良反应发生率为8.33%。两组不良反应发生率比较差异无统计学意义（P＞0.05）。

2.1.1 Applications of freeze-drying in cartilage TE

Freeze-drying is a commonly used processing method in TE technology, and the resulting scaffold materials generally have high porosity. For instance, crosslinked interpenetrating polymer network (IPN) hydrogels composed of sodium alginate and gelatin (SA/G)with 50 wt% NCC were prepared by freeze-drying(Fig.2)[18]. The crosslinking process was divided into two steps: the first step was to prepare a single crosslinked nanocomposite hydrogel (X SA/G/NCC)by crosslinking with CaCl2, and the next step was to obtain a double-crosslinked hydrogel (XX SA/G/NCC) by crosslinking with genipin. The results showed that X SA/G/NCC had high porosity (＞96%),high interconnectivity, and uniform pore distribution.Further, NCC was combined with a matrix to serve as templates for surface crosslinking, thus resulting in an optimal nanopore wall roughness beneficial to cell adhesion and extracellular matrix (ECM) production.In XX SA/G/NCC, a tighter network formed between the matrix phase and NCC, resulting in collapse of the pores on the surface. The second crosslinking process showed no significant effect on porosity, while the tight gathering of pore walls led to the formation of a layered structure with a broad pore size distribution (12～192 μm) and less interconnectivity compared with X SA/G/NCC. Therefore, XX SA/G/NCC could not be used as a template because the NCC network was destroyed.In general, the combination of NCC and crosslinking led to the improvement of mechanical properties of X SA/G/NCC. Compared with natural cartilage, X SA/G/NCC had a higher modulus and equivalent strain and strength, which enabled its use as cartilage substitutes.

Similarly, NCC-reinforced semi-IPNs of chitosan hydrogels were also developed by freeze-drying[19].NCC was distributed uniformly within the chitosan matrix, combining the amorphous and crystalline regions of the hydrogels. In terms of performance,the maximum compression of the chitosan hydrogels increased from (25.9±1) kPa to (50.8±3) kPa as the NCC content increased from 0 to 2.5%. However, the maximum compression did not increase significantly when the NCC content exceeded 2.5%. On the other hand, the composite hydrogels exhibited prominent pH sensitivity and produced maximum swelling ratio under acidic conditions (pH=4.01). NCC-chitosan hydrogels with improved mechanical properties and pH sensitivity could be applied in TE.

编目人员应该首先明确《中图法》文学类的体系结构和列类标准，遵循文学类的分类标引规则，才能准确掌握归类方法，将文学作品准确地归类。文学作品的分类路径可以概括为：在标引时先判别文体，再看是一人或多人的作品，再查出著者国籍，然后依国家、文体、总集或别集的标准，有必要时再按时代标准，顺次归类。

Cartilage tissue is a special type of tough and slightly elastic connective tissue, with a certain compressive rigidity and ability to facilitate moisture ingress,thus helping in cushioning the forces that bones are subjected to[16]. The cartilage tissue in an adult is distributed in the ears, nose, joints, ribs, and vertebrae,which lack lymphs, vessels and nerves; hence, the ability of cartilage to repair itself is greatly limited once damaged[17].

Importantly, NC shows promising properties in promoting printability and cell activity. A type of bioink that could be printed with high fidelity was created by combining NC with alginate sulfate, which could be employed to create complex three-dimensional (3D)structures[23]. NC was combined with alginate sulfate to improve the poor printability of alginate sulfate. The cartilage cells in alginate sulfate-NC gel discs were active, mitogenic, collagen II capable cells. Although the printing conditions affected the cell behavior greatly in this material, the conical needle with a wide diameter could best preserve the cellular function. Furthermore,a 3D bioprinting process for NC hydrogels loaded with human nasal chondrocytes (hNCs) was studied, which could be used for patient-specific auricular cartilage regeneration[24]. Besides, 3D printing using a NFC-alginate (NFC-A) bioink facilitated cell-supported biomanufacturing as well as patient-specific auricle constructs with open internal structures, high cell density, and uniform cell distribution. The NFC-A constructs loaded with cells exhibited excellent shape and dimensional stability as well as increased cell viability and proliferation properties in vitro. In addition,NFC-A bioink supported the redifferentiation of hNCs and the synthesis of cartilage-specific ECM components.

2.1.3 Applications of other methods in cartilage TE

Electrospinning is one of the most important methods in the synthesis of bone TE scaffolds, which can be applied to prepare microfibers and even nanofibers. The obtained materials can possess high porosity, which are beneficial to the mineralization and deposition of inorganic mineral crystals, and mimicking the natural ECM. Calcium phosphate is the main inorganic component of bone, and most researches on calcium phosphate are focused on hydroxyapatite (HAp),β-tricalcium phosphate (β-TCP), and the mixture of both in the preparation of bone TE scaffolds[31]. Some researchers studied the bio-simulated composite scaffold with mineralization of HAp based on electrospun poly(ε-caprolactone) (PCL)/NC fibers[32].With increasing content of NC, the average diameter of the composite fibers decreased and the conductivity of the mixture solution increased. On the other hand,NC could be applied as an additive to activate the biomineralization process, and might induce the deposition of HAp. The longer the mineralization time,the more the mineral crystals were formed. The scaffold could not only simulate the components of natural bone, but also improved the surface hydrophilicity, and could therefore be used for bone TE. By utilizing the electrospinning method, other nanocomposites were synthesized by incorporating poly(ethylene glycol)(PEG)-grafted NCC into poly(lactic acid) (PLA)[33]. The PLA/NCC-g-PEG scaffolds in which the weight percent of NCC-g-PEG was 5% on the basis of PLA had smaller nanofiber diameters with enhanced mechanical strength,and showed improved cell viability and proliferation,indicating an appealing application for bone TE.

In addition to freeze-drying and 3D printing, there are a number of processing methods that can be used in cartilage TE, including salt leaching, casting, and spin coating, to meet the requirements of different scaffold materials. Porous starch/NFC composites for cartilage TE were prepared by salt leaching[25]. The combination of nanofibers in the starch structures enhanced the attachment and proliferation of cells on the scaffolds.Furthermore, a high-strength microcrystalline cellulose(HS-MCC) hydrogel was synthesized from natural cellulose via three steps: dissolution, curing, and exchange[26]. Because of the physical entanglement of MCC in a solvent mixture of tetrabutylammonium fluoride/dimethyl sulfoxide (TBAF/DMSO), the viscosity was adjusted to synthesize the high-strength hydrogel. The highest viscosity was obtained when the contents of MCC and TBAF were 2.5% and 3.5%in cellulose solution, respectively, resulting in the strongest HS-MCC hydrogel, which had the potential for bio-related applications such as drug delivery vehicles and artificial cartilage.

Further, bio-elastic lubricating films of NFC and hyaluronic acid (HA) were developed, which showed appealing applications in cartilage implants[27]. The NFC dispersion was spin-coated on gold-plated quartz crystals to prepare thin films, and HA was covalently bonded to NFC membranes by esterification reaction,which improved the poor lubricating properties of the NFC membranes. In addition, the hydrogels were synthesized by forming a network of poly(2-hydroxyethyl methacrylate) (PHEMA) matrix enhanced with cellulose whiskers[28]. The hydrogels had enhanced toughness, increased viscoelasticity, and improved recovery behavior, which could be used for articular cartilage replacement. The applications of NC-based cartilage TE scaffolds are summarized in Table 1.

2.2 Bone TE

Bone is a kind of hard tissue that forms most of the skeletons of humans and vertebrates, and plays a major role in supporting physical activity and protecting internal organs. Bone tissue contains a large amount of calcium deposits in the cell matrix, which concentrates most calcium of the body. To maintain normal heart function, it is necessary to ensure a suitable concentration of blood calcium; here, bone tissue plays a crucial role in maintaining the calcium balance of blood[12]. The bone defects caused by trauma, surgery,infection, etc., are very common clinically, which bring great inconvenience and pain to patients. The functional requirements of bone need bone TE scaffolds to possess good biocompatibility and osteoinduction in addition to adequate mechanical support[29]. As a biomass material, NC can be extracted from different kinds of wastes including paper residue[30], which is green and renewable, and combines excellent mechanical properties with compatibility, opening a new avenue for bone TE.

2.2.1 Applications of electrospinning in bone TE

为使S7-200 PLC与变频器能够正常通讯，不仅要编写PLC的通讯程序，还需要对变频器的参数做正确的设置，正确建立两者之间的物理接线方式，才能够实现通讯的目的[7]。

近年来，迫于世界性经济下滑，贸易保护主义抬头，加之我国总体经济步入新常态，对外贸易的增速持续下降。我国同多数发达国家一样，在多哈回合谈判停滞的背景下，正着力签署及推行各类双边及多边贸易协定，尤其是加紧与周边国家签署RTA协议，以保持我国经济平稳发展，带动亚太和全球经济增长。

Besides the ESC synthesized from NFC and NCC,the ESC prepared from electrospinning of cellulose derivatives also has important applications. By using the novel solvent combinations, such as acetone/ethanol and dimethylformamide (DMF)/tetrahydrofuran (THF)/acetone, electrospun nanofiber scaffolds of cellulose acetate phthalate (CAP) were produced[34]. The scaffolds combined several prominent characteristics,including sufficient stability and strength, proper porosity, and uniformly distributed nanofibers; thus,the CAP scaffolds had been standardized for 3D culture of chondrocytes. In addition, thick scaffolds could be developed by extending the collection time(90 min) to further optimize the mechanical properties of scaffdds. Furthermore, electrospun cellulose/nano-HAp nanocomposite nanofibers (ECHNN) were prepared,which had excellent mechanical properties and increased thermal stability when nano-HAp was added,and were beneficial to the adhesion and proliferation of human dental follicle cells[35]. Therefore, ECHNN might have potential applications in bone TE. In another research, randomly oriented nanofiber scaffolds of modified cellulose (MC) and polyvinyl alcohol (PVA)were synthesized by electrospinning[36]. Compared with pure PVA, the crystallinity of the nanofibers decreased as the PVA content decreased. The nanofibers with lower crystallinity were more advantageous for bone TE. For the β(1→4) glycosidic bond of the MC structure, a peak appeared at 770 cm-1, which exists for the natural skeletal structure; therefore, they were expected to be used for bone TE. However, cytotoxicity studies were not conducted in this work. Afterward,these researchers prepared hydroxyethyl cellulose(HEC)-based nanostructured scaffolds with a uniform fiber morphology, and PVA was employed as the ionic solvent to support the electrospinning of HEC[37]. The mechanical properties of composites were significantly affected by HEC. Increasing the HEC content resulted in an increase in elastic modulus and tensile strength,while the elongation at break decreased proportionally.In addition, the cell viability increased, and cell proliferation was significantly promoted at a high HEC concentration.

Overall, the ESC derived from CA plays an important role in promoting cell proliferation, differentiation,and mineralization. For instance, artificial bone tissue scaffolds based on CA and nano-HAp natural hybrids were prepared by electrospinning[38]. The CA-HAp nanoscaffolds promoted the adhesion and growth of osteoblasts and stimulated the cells to exhibit functional activity. The morphologies and structures of scaffolds played important roles in promoting cell activities and enhancing apatite mineralization. By utilizing a series of processes, including electrospinning, saponification, and in situ hydrolysis, 3D cellulose sponges based on CA were synthesized[39]. The cellulose sponges showed the ability of nucleating active calcium phosphate (Ca-P)crystals in simulated body fluid (SBF), and the minerals deposited on nanofibers had a similar composition to that of HAp. On the other hand, the sponges exhibited better cell infiltration and proliferation than 2D cellulose mats, and were therefore expected to be applied in bone TE. These researchers also prepared a cellulose-reinforced nylon 6 (N6) nanofibrous film by electrospinning and saponification[40]. Cellulose was regenerated in situ by the alkaline saponification of CA of hybrid fibers to synthesize cellulose-enhanced N6 (nylon 6/cellulose, i.e., N6/CL) nanofibers. As the content of CA in the electrospinning solution increased,the fiber diameter and pore diameter gradually decreased. The regeneration of cellulose improved the nucleating ability of bioactive calcium phosphate crystals in the SBF. However, in Joshi’s study, only in vitro mineralization experiments were performed,and the requirement of researches on compatibility and degradability still remains. In addition, graphene oxide (GO)-CA nanofiber scaffolds were prepared in another study, which might also be used in bone TE[41]. With the incorporation of GO, the Young’s modulus of the nanofibers increased, and the adhesion and proliferation of human mesenchymal stem cells(hMSCs) on the scaffolds were significantly improved.Biomineralization had also been prominently optimized with the doping of GO in nanofibers. Accelerated biomineralization on GO-CA nanofibers led to a significant increase in the activity of biomineralizationassociated alkaline phosphatase, and therefore induced the osteogenic differentiation of hMSCs.

Apart from CA, the applications of ESC based on CMC in bone TE are also very extensive. In one research, polysaccharide-based electrospun nanofiber composites with HAp were prepared, and the formation conditions of nanofibers from CMC and polyethylene oxide (PEO) were systematically studied[42].It was determined that a mixture of 7 wt% CMC and 5 wt% PEO at a ratio of 50/50 (V/V) under suitable electrospinning parameters (low humidity and high voltage) could obtain uniformly shaped nanofibers with a diameter distribution between 150～200 nm. The HAp nanoparticles (nHAp) were then incorporated into the nanofibers by preparing a nHAp dispersion in the CMC/PEO mixture and subsequently spinning into fibers. The nHAp/CMC/PEO composites were nontoxic and biocompatible at a concentration of 0.03 wt%.Moreover, the nanofibers were further hydrophobized by their reaction with alkenyl succinic anhydride (ASA),which rendered them insoluble in water; however, they partially retained their morphology. Cells growing on the hydrophobized fibrous webs showed similar viability but reduced cell attachment compared with the cells growing on commercially available collagen/apatite scaffolds. The results confirmed that CMC/PEO/nHAp nanocomposites would have potential applications in regenerative medicine if surface modification, degradation, solubility, and mechanical properties of the material were further optimized.In another research, a silk fibroin (SF) and CMC composite nanofibrous scaffold was developed by free liquid surface electrospinning[43]. The SF/CMC scaffold had excellent cell-supporting properties, with improved osteoblast differentiation ability compared with pure SF. Moreover, an electrospun HAp-coated CMC scaffold (HAp/CMC) was successfully prepared[44]. The HAp/CMC nanofibers showed different morphologies with the differences of the NaOH concentration during carboxymethylation, the HCO3- concentration of SBF,and the mineralization time. As the seeding time increased, the osteoblast MC3T3-E1 cells on the HAp/CMC mats proliferated. The results indicated that the HAp/CMC scaffold could promote bone regeneration.The NC-based bone TE scaffolds prepared by electrospinning are summarized in Table 2.

2.1.2 Applications of 3D printing in cartilage TE

2.2.2 Applications of freeze-drying in bone TE

The scaffold materials synthesized by freeze-drying can also have a high porosity, with good mutual connectivity between the pores, which is beneficial for seeding cells for various physiological activities. In addition,the freeze-drying process can maintain the structure and morphology of scaffolds betterly, and thus has wide applications in bone TE. Kumar et al conducted a series of studies on the applications of NCC-reinforced composite scaffold materials in bone TE. They used the freeze-drying method to prepare a NCC-reinforced PVA/silica glass hybrid scaffold at first[45]. The scaffold combined a highly porous structure with good pore connectivity. With increasing content of NCC and the subsequent addition of silica-based bioactive glass, the stiffness of the hybrid scaffold significantly increased.In addition, the incorporation of bioactive glass did not alter the overall microstructure of the PVA/SG/NCC scaffold; however, the crystallinity decreased, making it suitable (as the amorphous area) for bone regeneration.Moreover, a PVA/SG/NCC scaffold possessed better cell adhesion and growth characteristics than the PVA/NCC scaffold. However, further analysis of biocompatibility in vivo is required. Afterward, a NCC-reinforced polyacrylamide (PAAm)/sodium alginate/silica glass hybrid hydrogel with good compression stiffness was also synthesized[46]. The obtained hydrogel exhibited a high porosity and an interconnected pore structure after freeze-drying. The addition of NCC (2.5～10.0 wt%) improved several properties of hydrogel, including thermal stability, mechanical properties, and degradation stability in vitro, and also afforded good cell activities in vitro on hydrogels without influencing the apatite-forming ability in SBF. Furthermore, this group prepared NCC and/or halloysite nanotube (HNT)-reinforced sodium alginate(Alg) and xanthan gum (XG)-based nanocomposite scaffolds by freeze-casting/drying[47]. All the scaffolds exhibited high porosity and pore interconnectivity.Compared with Alg and AlgX scaffolds without NCC and/or HNTs, the nanocomposite scaffolds had improved thermal stability, compressive strength, and cell compatibility. On the other hand, XG/bioactive silica glass (SG) hybrid scaffolds reinforced with NCC were found to be highly porous and had adjustable and improved mechanical stability under dry and wet conditions compared to pure XG scaffolds as well as good cell compatibility. Therefore, the scaffolds might show appealing applications in low-load bone TE[48].

In addition, another special material can be utilized for bone regeneration, which is bioactive glass. Since Hench, a professor at the University of Florida, developed the first generation of bioactive glass, its use in bone repair has become increasingly widespread. For example, pure cellulose, methyl cellulose, and amine-grafted cellulose were used as templates for the synthesis of bioactive glass nanoparticles[59]. Amine grafted cellulose and pure cellulose promoted the formation of in situ nanoparticle composites, while methyl cellulose was considered an outstanding sacrificial template for synthesizings the uniform nanoparticles with diameters in the range of 55 nm, which resulted in the combined properties of the bioglass, including excellent biological activity, damping properties, and mechanical stiffness. Depending on the template types, the HAp of each phase treated by SBF was observed to be crystalline, showing strong bone bonding ability. The abovementioned researches are summarized in Table 4.

From the abovementioned researches, it can be confirmed that NC can not only enhance the scaffolds,but is also nontoxic, thus contributing to the adhesion and proliferation of cells. Further, NC is beneficial to the mineralization and deposition of inorganic components, and thus shows potential applications in bone TE. In addition, PAAm is commonly used to graft and modify cellulose to prepare nanocomposites.For example, a semi-IPN cellulose-graft PAAm/nano-HAp nanocomposite scaffold was synthesized by free radical polymerization and freeze-drying[50]. The pores on the scaffold were interconnected, and after soaking in SBF, apatite particles were well deposited on the interconnected irregular pores. The obtained semi-IPN nanocomposite scaffold could be combined with living bone by forming an apatite layer on its surface,and can thus be applied in bone TE. Moreover, a novel porous 3D nanocomposite scaffold was prepared,which was composed of cellulose-graft-PAAm (Celg-PAAm) and nanopowders of HAp (n-HAp)[51].The n-HAp/Cel-g-PAAm scaffold exhibited higher mechanical strength than that of a trabecular bone, and the scaffold extraction was not cytotoxic and had good biocompatibility.

In another research, a simvastatin-loaded gelatin-NC-β tricalcium phosphate hydrogel scaffold was developed by freeze-drying, which combined osteoconductivity with osteoinductive properties and could be applied in promoting bone regeneration[52].NFC resulted in a slower rate of degradation and was beneficial to the sustained release of simvastatin. The GNTS.5 scaffold and its osteoconductive structure could release an optimal concentration of simvastatin to enhance osteogenic activity. The bone TE scaffolds prepared by freeze-drying are listed in Table 3.

Yeelink是由青岛一家互联网公司免费开放的物联网平台，类似于国内的乐联网、机智云、中国移动物联网、传感云等平台一样；需要经过相关设置便可接入用户的设备，它是一个安全可靠的云存储平台，会保留用户提交的每一条数据，并且支持多平台接入。Yeelink的优点是将复杂的传感器数据以简便的方式组合到一个网络内。Yeelink与用户的设备连接方式简单，云服务流程如图13所示。

2.2.3 Applications of other methods in bone TE

Hard tissue and soft tissue are relatively different,and the former is denser and harder than the latter.Hard tissue mainly includes skeletons and teeth that possess hard structures and are formed through biomineralization, and the skeletal system can be divided into two parts: bones and cartilages[12].Compared to the functional requirements of soft TE materials, hard TE usually pays more attention to improving the mechanical properties and stability.

Anthony[19]提出了教学方法的三个层次：教学理论(approach)、教学方法(method)和教学技术(technique)。张老师关注后两个层次，即具体的组织课堂和管理课堂的方法。她摆脱对某种教学理论的依赖，注意具体的课堂教学活动的设计，思考、创造“自己的”、“具体的”、可操作的教学技术，向“将课堂教学理论化，将教学理论实践化”转化，试图把个人的实践上升到理论的高度。学生信念和教育信念是反思的主要目标。

In addition, to evaluate the use of waste paperderived NCC in bone TE, the NCCs produced from the hydrolysis of bagasse-derived cellulose by hydrochloric acid, sulfuric acid, and phosphoric acid were also evaluated, and NCCs with different surface compositions were used to produce biomimetic growth HAp[55]. The sulfonate and phosphonate groups on the surface of the NCC had a direct effect on the nucleation and growth of HAp. The differences in HAp deposition contents and surface areas indicated that sulfonate and phosphonate groups were directly involved in the growth of HAp on NCC. The materials prepared by the biomimetic method had higher biocompatibility/biological activity compared with the materials synthesized by the wet chemical precipitation methods.On the other hand, NCC was obtained by extracting the integuments of tunicate by means of sulfuric acid hydrolysis, which were found to be useful for adhesion, growth, and differentiation of osteoblasts without cytotoxicity[56]. The results indicated that intracellular calcium flux was associated with the increased differentiation of NCC under mechanical stress, confirming the applicability of NCC in bone TE, and a complex system for osteoblast growth and differentiation based on NCC was developed.

A study was conducted to research the effects of cellulose-nanodiamond conjugates, biocompatibility,and surface functionalization on the activities of osteoblasts[57]. The cellulose-nanodiamond composites,which were called oxidized biocompatible interfacial nanocomposites (oBINC), had the capacity to act as bio-interface materials because of their osteoconductive properties and biocompatibility. The related properties of oxidized nanodiamonds (oND) were improved by their covalent bonding with silylated NCC, exhibiting better activities of human fetal osteoblastic (hFOB)1.19 cells than the precursor materials. Moreover, the injectable heat-sensitive chitosan/glycerophosphate(CS/GP) hydrogels supplemented with TEMPO-oxidized cellulose nanofiber (TOCNF) were prepared for bone regeneration[58]. To resolve the limitation of the balance between biocompatibility and thermal gel properties of the CS/GP thermo-sensitive hydrogel system, TOCNF was added as an additive into the hydrogel. These hydrogels could undergo sol-gel transitions at body temperature through the interaction between chitosan and β-glycerophosphate, and the addition of TOCNF led to faster gelling times and increased porosity. Furthermore, TOCNF could significantly improve the biocompatibility of chitosan hydrogel as a biomaterial for biomedical applications.

In addition, NFC-enhanced gelatin scaffolds were synthesized by carbodiimide crosslinking chemistry and freeze-thawing[49]. The scaffolds possessed suitable microstructures, osteoid-like compressive strength, and elasticity, and could cause calcium deposition. Introducing 3-aminopropylphosphoric acid(ApA) moieties into the NFC further enhanced and facilitated the deposition of HAp-like crystals on the scaffolds. These materials had no cytotoxic effect on mesenchymal stem cells.

其次，科学亦有自身的价值取向和精神追求。科学的精神追求主要体现在对于真理和人类福祉追求。科学本质上是不断探索真理的过程，这主要体现在科学家对于真理的追求和捍卫。比如，布鲁诺为了坚持日心说，宁愿被烧死，也要捍卫真理，便是对科学家追求真理的最好证明。真正的科学还关心人类的福祉。

2.3 Dental TE and restoration

In oral and maxillofacial tissues, a tooth is the highly differentiated component in organisms and is slowly developed from the tooth germ tissue located in the jaw,including enamel, dentin, cementum, and dental pulp.Its formation is regulated by an extremely complex network of delicate signaling molecules, including a series of epithelial-mesenchymal interactions and toothgenerating molecular events. The tooth has received extensive attention owing to its structural complexity and functional specificity[60-62]. Teeth grow twice during the human life: the first growth is called deciduous teeth, and after they fall off, they are replaced with permanent teeth. Once the permanent teeth are lost,they cannot be regenerated. Due to aging or some oral and systemic diseases such as periodontitis, teeth loss often occurs, resulting in discounting of human oral health and causing a lot of inconvenience in life at the same time.

To solve the problem of teeth loss, denture restoration is often used in clinical practice. However, it is not an ideal solution because of its poor functionality and difficulty in retention, coupled with safety and service life issues. At present, with the development of materials science and biomedical technology, glass ionomer cement (GIC), which is a kind of material for repairing, bottoming, and bonding of teeth defects, is gradually being widely used in oral clinical practice.However, because of the poor mechanical properties of the cementitious materials, research and development in materials science has focused on improving the mechanical strength of materials while maintaining their excellent performance.

Because of insufficient mechanical strength,general GIC materials are mostly used for bonding,and filling and repair of anterior teeth and deciduous teeth. By adding cellulosic fibers to GIC, the material structures were changed and the mechanical properties were improved, rendering it applicable for chewing and repairing posterior teeth, especially in atraumatic restorative treatment (ART) technology[63]. The researchers analyzed GIC (control) and three different types of GIC modified with cellulose fibers (GICMF):GICMF1, GICMF2, and GICMF3. The composites exhibited similar water absorption and solubility as GIC, and no signs of disintegration were observed.Although GICMF2 provided better compression resistance, abrasion resistance, and adhesion, it did not interfere with the diametral tensile strength. The analysis of GICMF2 illustrated that the interaction between fibers/ionomer matrix/loading particles formed new stable composites. Afterward, cellulose microfibers(CMF) and NCC were employed to reinforce dental GIC[64]. The addition of CMFs to the matrix did not improve the mechanical properties of GIC significantly,but the addition of a small amount of NCC into the GIC significantly improved the mechanical properties,including elastic modulus, diametral tensile strength,and compressive strength.

However, the abovementioned studies are mainly aimed at improving the mechanical properties of the composites. Compatibility and cytotoxicity tests in vitro and in vivo are also required before clinical applications.Therefore, researchers evaluated the biocompatibility of commercial dental GIC mechanically reinforced with CMFs (GIC+CM) or NCC (GIC+CN)[65]. Their results confirmed that all biomaterials showed satisfactory biocompatibility; however, the GIC modified with NCC showed outstanding tissue repairing function.

In addition, composites of polyacrylonitrileelectrospun nanofibers containing NCC were prepared by electrospinning, which could be used as reinforced dental resins[66]. The addition of 3% NCC resulted in higher tensile properties of the electrospun fibers,which showed appealing applications in reinforcing dental composites by nanofiber incorporation.Similarly, an ESC web for dental materials was also synthesized by electrospinning and possibly used as an aesthetic orthodontic scaffold material or a veneer for restorative dentistry[67]. The non-defective nanofibers were successfully electrospun into flat membranes by using acetone and CA polymer and DMAc solutions.The increased charge density of the electrospinning jet resulted in a decrease in the average fiber diameter.However, the infiltration of nanofiber web with Concise resin and epoxy resin has not yet improved the flexural strength of composites. The reason is speculated to be incomplete wetting of the fibers by the resin component,and air inclusions. Therefore, further reduction in air inclusions is required to determine the enhanced effect of the CA nanofibers.

In view of the problems of teeth loss, apart from material repairing, there is another important approach to reconstruct biologically active teeth to repair the missing teeth by artificial methods. The rapid development of TE technology is a great opportunity to complete this vision. Dental TE, a kind of TE technology that can be applied to dental restorations and teeth regeneration, is demonstrating thriving vitality. For instance, doxycycline-loaded chitosan/HAp/hydroxypropylmethyl cellulose (HPMC) spongy scaffolds were prepared by freeze-drying, which were non-toxic and could promote the viability of pre-osteoblasts[68]. Moreover, the scaffolds showed compressive strength of 14 MPa/cm3 and could be used as a substitute for alveolar bone and promote the formation of mineralized tissue.

在节能项目的执行上，实行专业负责人制，每一个项目的参与人员由专业负责人和项目管理小组人员共同构成，负责对项目进行规范化管理。

3 Conclusions and overview

Nanocellulose (NC), a kind of green biomass material,can be obtained by extracting and processing cellulose that is widely synthesized by animals, plants, and microorganisms in nature by means of mechanical and chemical methods. As NC has excellent mechanical properties, it can be compounded with gelatin, polyester,PVA, etc., and is widely used as a reinforcing phase for composite materials. With prominent biocompatibility and degradability, NC has attracted much attention in biomedical applications, especially in tissue engineering (TE) scaffolds. Unlike the functionalities required for soft TE materials, the hard TE scaffolds require high mechanical properties, which can enhance the performance of NC and broaden its application prospects in hard TE. In addition, NC can be used for the adhesion, growth, and differentiation of osteoblasts,and to promote ossification. When compounded with other substances, it may promote the mineralization and deposition of hydroxyapatite (HAp), the main inorganic component of bone. At the same time, composites with different shapes and the desired characteristics of hard TE scaffolds can be prepared by kinds of methods such as electrospinning, freeze-drying, and 3D printing,making the scaffolds more controllable and adaptable.In general, TE, a cross-cutting-edge technology that integrates numerous sciences including life science,engineering, and materials science, aims to overcome the limited source of implants and post-implantation immune rejection that need to be urgently resolved.Therefore, its impact on biomedical science is profound.As a sustainable bio-based nanomaterial, NC combines the advantages of compatibility and degradability,which is superior to other artificial synthetic materials.The prospect of applying NC to the construction of TE scaffolds is obvious. However, the TE technology is currently immature. Moreover, there is a big difference between artificially induced tissues and normal tissues,and the understanding of growth, maturation, and function of native tissues is not deep enough. Thus,there is still a long way to explore TE in the future.

1.3 观察指标 观察两组患者住院天数、住院费用及术后并发症等指标。统计两组患者对护理工作满意率及对健康教育满意率。其中护理工作满意率调查使用本院自制的“住院患者满意度调查表”:对护士服务态度、操作技术、病情观察、隐私保护等方面进行调查询问。健康教育满意率调查使用本院自制的“住院患者健康宣教满意度调查表”:对护士入院宣教、饮食指导、用药指导、检查指导及围手术期指导等方面进行调查询问。患者健康知识评分采用本院自制的“住院患者健康知识测评表”:对疾病诱发因素、常见表现、自我保健等方面进行调查。

Acknowledgments

Financial support was provided by the special fund for Independent Innovation and Industry Development in the Core Area in Haidian District of Beijing (255-kjc-020).

5）长沙地区雷电灾害高风险区主要分布在长沙县、宁乡县、望城区等地，低风险区位于长沙市芙蓉区、开福区、雨花区等地。

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