涂小林，重庆医科大学生科院骨发育与再生研究平台主任、二级教授、博导。美国印第安纳大学医学院永久兼职教授。国务院特殊津贴专家，国家百千万人才工程人选、有突出贡献中青年专家；重庆市百人计划特聘专家、首席专家工作室领衔专家、学术技术带头人(骨科)；获中国侨界贡献奖二等奖，重庆市科技进步一等奖、渝中区首批“渝中英才”。

     兼任中华医学会骨科学分会基础组委员、骨松与骨矿盐疾病分会基础组委员；中国老年医学学会骨松分会创新转化组常委、重庆市骨内科学组副主委；中国研究型医院学会骨科创新转化分会委员、基础组常委；中国康复医学会再生医学与康复专委会委员；中国生物材料学会先进制造分会委员。

     从事干细胞与骨发育、再生医学研究20余年。在Nat Med、Bioact Mater、Dev Cell、PNAS、Biodes Manuf等刊物发表骨科研究论文30余篇，引用率高。2014年全职回国，组建骨发育与再生科研团队，现有固定成员8人，博士及硕士研究生19人。主持国家自然科学基金-广东联合基金重点项目1项、面上项目2项，重庆市基础研究重点项目1项等。前期成果入选美国骨矿盐疾病研究学会(ASBMR)2013年度杰出研究，文章被《Nature Reviews》系列杂志连续专题报道。

     研究运动系统衰老、退变与再生康复，并开展转化应用研究。研发了硬材料与细胞一体化3D生物打印技术与装备。构建活体细胞、脱细胞基质、外泌体以及微环境因子功能模块，修复骨缺损。探索云端打印、标准化生产骨修复功能模块/骨类器官。挖凿小分子药物并开展转化研究。

Topic title: Bioprinting metabolic and neurovascularized bone organoid for regenerative repair

Abstract:

The artificial reconstruction of simulated bones with dual functions of mechanical support and authentic bioactivities, including bone formation and resorption, remains a huge challenge for orthopedic regenerative medicine. Scientists have successfully used functional cells or growth factors to simulate the microenvironment of tissue/organ development, guiding stem cell differentiation and self-assembly to construct organoids (Nat Rev Mater 2019, 4:606). Among these organoids, the optical cup has been used in the clinical treatment of macular lesions to restore patients’ vision (Trends Mol Med 2022, 28:388). Therefore, in this regard, building authentic skeleton requires physiological osteogenic microenvironments (POME).

In 2016, an integrated tissue-organ printer was able to biologically generate structures of the supporting hard materials and stem cells with clinically relevant size, shape, and structural integrity, which were implanted into murine skulls to form vascularized bone (Nat Biotechnol 2016, 34:312). This work is considered as a milestone of orthopedic medicine and opens up a novel avenue for future medical applications. However, seven years later, this study did not make further breakthroughs in bone reconstruction, possibly due to a lack of application in the POME (Chem Rev 2020, 120:11056).

Here, we constructed a bone developmental module (BDM) using an ourself-developed hard material and cell integrated 3D bioprinting system (Biodes Manuf 2022, 5:487). This module utilizes supporting materials with improved physical and chemical properties, biocompatibility, and nutrient and metabolite channels for cell growth, as well as a POME we discovered (PNAS 2015, 112:e478). The POME is the osteocyte with dominant active Wnt/β-catenin signaling, called daCOOME. The elastic modulus of the module is 11.3 MPa, and the calcium:phosphorus ratio is 1.5, reaching the strength and biocompatibility of murine cancellous bone. Additionally, the hydrogel loaded with cells is consolidated by double crosslinking in BDM, and the channels between the hydrogels are prefabricated by sacrificial material Pluronic F-127, which ensures that the cells grow ex vivo for up to 28 days, and the cell survival rate in the first 7 days is as high as 92%. daCOOME promotes cell proliferation, osteogenic differentiation and mineralization of bone marrow stromal cells, and produces VEGF and NGF, recruiting HUVEC and nerval progenitor cells for angiogenesis and neurogenesis. In vivo, the BDM forms a bone organoid, containing osteoblasts, osteoclasts, H-type blood vessels, and the cells that express neural markers, such as β3-tubulin and NeuN as authentic bone develops. The BDM conforms to bone mechanics and accelerates the repair of critical-sized defects of parietal bone, providing a promising strategy for orthopedic regenerative medicine.