Self-assembling process in tissue engineering of articular cartilage

关节软骨组织工程中的自组装过程

• 批准号: 9755352
• 负责人: Kyriacos A Athanasiou
• 金额: $ 40.03万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9755352
• 关键词: Address; Allogenic; Animal Model; Animals; Arthroscopy; Autologous; Autopsy; Biochemical; Biochemistry; Biological; Biology; Biomechanics; Biomimetics; Cartilage; Cartilage injury; Cell Count; Cells; Chondrocytes; Chondroitin ABC Lyase; Clinical Research; Collagen; Complex; Cyanoacrylates; Data; Defect; Dose; Effectiveness; Engineering; Ensure; Evaluation; Exhibits; Foundations; Friction; GAG Gene; Glues; Grant; Guidelines; Histology; Human; Hydrostatic Pressure; Immune response; Implant; In Vitro; Knee; Knee bone; Lateral; Link; Magnetic Resonance Imaging; Mechanics; Medial; Methods; Modeling; Morphology; Mus; Natural regeneration; Oryctolagus cuniculus; Phase; Phenotype; Preparation; Process; Property; Protein-Lysine 6-Oxidase; Protocols documentation; Publications; Recommendation; Safety; Series; Serologic tests; Sheep; Solid; Stimulus; Surface; Surgical sutures; Technology; Testing; Tissue Engineering; Tissues; United States National Institutes of Health; Validation; Work; articular cartilage; base; bone; cartilage regeneration; clinically translatable; crosslink; design; dosage; good laboratory practice; healing; implantation; improved; improved functioning; in vivo; indexing; innovation; insight; interfacial; knee replacement arthroplasty; mouse model; novel strategies; osteochondral tissue; pre-clinical; public health relevance; repaired; research clinical testing; response; sample fixation; scaffold; scale up; success; synergism; systemic toxicity

 DESCRIPTION (provided by applicant): The self-assembling process in articular cartilage is emerging as a potentially robust approach for engineering large and small cartilage constructs. The objective of this proposal is to evaluate self-assembled articular cartilage in resurfacing the patella by quantifying the biologic response (i.e., host response to the construct), dose response (i.e., identifying the minimum number of necessary cells), and durability (i.e., stability, integriy, and maturation over a year), as defined by the FDA. Statistical optimization to improve the functionality of self- assembled cartilage constructs has yielded a powerful combination of externally applied stimuli that result in constructs with biomechanical and biochemical properties on par with those of native cartilage. Among a multitude of helpful stimuli, three have emerged as quite potent: hydrostatic pressure (10MPa at 0Hz during days 10-14), TGF-ß1 (30 ng/ml for 2 wks), and chondroitinase ABC (applied at 2 wks), applied in combination. Mechanisms linking these stimuli to the engineered tissues' biomechanical properties have also been elucidated to explain their synergisms and to consolidate them into simple culture protocols. A functionality index (FI) allowing the establishment of quantitative success criteria and validated for the comparison of constructs to native tissue showed that construct properties have attained FI values approaching 1, the value of native tissue. Based on these promising results and additional in vivo murine, leporine, and ovine data, this proposal will investigate the global hypothesis that constructs will show durability without an adverse host response via three aims: The objective of Aim 1 is to use a short-term (12wks), leporine patella resurfacing model to examine the hypotheses that: 1) not only will constructs retain stability and integrity in vivo, thir FI values will be improved by implantation, and 2) neither the allogeneic cells nor the culture products will elicit adverse host responses (local/systemic). Aim 2 employs the murine model to validate that implant scale-up would not alter neocartilage biomechanical properties. Aim 2 will also address certain challenges that are common across diverse cartilage regeneration strategies, namely initial fixation, subsequent integration, and durability against wear; these issues will be tackled using a chondroconductive glue, exogenous lysyl oxidase, and the chondrotuning method that yields robust and lubricious implants. Finally, Aim 3 will test the hypothesis that durable healing can be achieved for up to 12 months in an ovine model. This aim will also identify a minimum cell number that can be employed to achieve effective healing at 1 year. By following FDA's guidance document ("Preparation of IDEs and INDs for products intended to repair or replace knee cartilage"), and if the proposed study's hypotheses are proven, the results will provide exciting validation of the clinical translatability of self-assembed articular cartilage constructs.

 描述（由适用提供）：关节软骨中的自组装过程正在成为工程大型和小软骨结构的潜在强大方法。该提案的目的是评估自组装的关节软骨在重新铺面时 通过量化生物学反应（即宿主对构建体的响应），剂量反应（即识别必要细胞的最小数量）和耐用性（即稳定性，整数和成熟一年）来量化patella。统计优化以提高自组装软骨构建体功能的统计优化产生了外部应用刺激的强大组合，从而导致具有生物力学和生化特性的构造与天然软骨的构建体。在多种有用的刺激中，三种出现了很大的潜力：静水压力（在10-14天，在0Hz时为10MPa），TGF-ß1（2 wks的30 ng/ml）和软骨素酶ABC（在2 wks上施加2 wks），结合使用。将这些刺激与工程组织的生物力学特性联系起来的机制也已被阐明，以解释其协同作用并将其巩固为简单培养方案。功能指数（FI）允许建立定量成功标准并通过对天然组织进行比较的验证，表明构造特性已达到接近天然组织的值1的FI值。 Based on these promise results and additional in vivo murine, leporine, and ovine data, this proposal will investigate the global hypothesis that constructs will show durability without an adverse host response via three aims: The objective of Aim 1 is to use a short-term (12wks), leporine patella resurfacing model to examine the hypotheses that: 1) not only will constructs retain stability and integrity in vivo, thir FI values ​​will be通过植入改善，2）同种异细胞和培养产物都不会引起不良宿主反应（局部/全身）。 AIM 2采用鼠模型来验证植入物的扩大不会改变新机构生物力学特性。 AIM 2还将应对在潜水员软骨再生策略中常见的某些挑战，即初始固定，随后的整合和防止磨损的耐用性；这些问题将使用软骨导胶，外源性赖酰基氧化物以及提供坚固且易润滑的叶子的软骨结构方法来解决。最后，AIM 3将检验以下假设：在卵巢模型中最多可以在12个月内实现耐用的愈合。该目标还将确定可在1年在1年内实现有效愈合的最低单元格数。通过遵循FDA的指导文档（“为旨在修复或替换膝盖软骨的产品制备和INDS的制备”），如果证明了拟议的研究的假设，结果将为自组装的关节软骨结构的临床转换性提供令人兴奋的验证。

项目成果

Engineering large, anatomically shaped osteochondral constructs with robust interfacial shear properties.

• DOI: 10.1038/s41536-021-00152-0
• 发表时间: 2021-08-06
• 期刊: NPJ Regenerative medicine
• 影响因子: 7.2
• 作者: Brown WE;Huang BJ;Hu JC;Athanasiou KA
• 通讯作者: Athanasiou KA

Articular cartilage tissue engineering: the role of signaling molecules.

• DOI: 10.1007/s00018-015-2115-8
• 发表时间: 2016-03
• 期刊: Cellular and molecular life sciences : CMLS
• 作者: Kwon H;Paschos NK;Hu JC;Athanasiou K
• 通讯作者: Athanasiou K

Multimodal fluorescence lifetime imaging and optical coherence tomography for longitudinal monitoring of tissue-engineered cartilage maturation in a preclinical implantation model.

• DOI: 10.1117/1.jbo.28.2.026003
• 发表时间: 2023-02
• 期刊: JOURNAL OF BIOMEDICAL OPTICS
• 影响因子: 3.5
• 作者: Zhou, Xiangnan;Haudenschild, Anne K.;Li, Cai;Marcu, Laura
• 通讯作者: Marcu, Laura

Shear stress induced by fluid flow produces improvements in tissue-engineered cartilage.

• DOI: 10.1088/1758-5090/aba412
• 发表时间: 2020-08-10
• 期刊: Biofabrication
• 影响因子: 9
• 作者: Salinas EY;Aryaei A;Paschos N;Berson E;Kwon H;Hu JC;Athanasiou KA
• 通讯作者: Athanasiou KA

Cell-based tissue engineering strategies used in the clinical repair of articular cartilage.

• DOI: 10.1016/j.biomaterials.2016.04.018
• 发表时间: 2016-08
• 期刊: Biomaterials
• 影响因子: 14
• 作者: Huang BJ;Hu JC;Athanasiou KA
• 通讯作者: Athanasiou KA