Tissue Engineering Strategies Research Articles

Scaffolding Strategies for Tissue Engineering and Regenerative Medicine Applications: MABAC Method and Hamacher Aggregation Operators for Circular q-Rung Orthopair Fuzzy Decision-Making Problems

Scaffolding Strategies for Tissue Engineering and Regenerative Medicine Applications: MABAC Method and Hamacher Aggregation Operators for Circular q-Rung Orthopair Fuzzy Decision-Making Problems

Immune-cell-mediated tissue engineering strategies for peripheral nerve injury and regeneration.

During the process of peripheral nerve repair, there are many complex pathological and physiological changes, including multi-cellular responses and various signaling molecules, and all these events establish a dynamic microenvironment for axon repair, regeneration, and target tissue/organ reinnervation. The immune system plays an indispensable role in the process of nerve repair and function recovery. An effective immune response not only involves innate-immune and adaptive-immune cells but also consists of chemokines and cytokines released by these immune cells. The elucidation of the orchestrated interplay of immune cells with nerve regeneration and functional restoration is meaningful for the exploration of therapeutic strategies. This review mainly enumerates the general immune cell response to peripheral nerve injury and focuses on their contributions to functional recovery. The tissue engineering-mediated strategies to regulate macrophages and T cells through physical and biochemical factors combined with scaffolds are discussed. The dynamic immune responses during peripheral nerve repair and immune-cell-mediated tissue engineering methods are presented, which provide a new insight and inspiration for immunomodulatory therapies in peripheral nerve regeneration.

Synergy between 3D-extruded electroconductive scaffolds and electrical stimulation to improve bone tissue engineering strategies.

In this work, we propose a simple, reliable, and versatile strategy to create 3D electroconductive scaffolds suitable for bone tissue engineering (TE) applications with electrical stimulation (ES). The proposed scaffolds are made of 3D-extruded poly(ε-caprolactone) (PCL), subjected to alkaline treatment, and of poly(3,4-ethylenedioxythiophene):poly(styrene sulfonate) (PEDOT:PSS), anchored to PCL with one of two different crosslinkers: (3-glycidyloxypropyl)trimethoxysilane (GOPS) and divinyl sulfone (DVS). Both cross-linkers allowed the formation of a homogenous and continuous coating of PEDOT:PSS to PCL. We show that these PEDOT:PSS coatings are electroconductive (11.3-20.1 S cm-1), stable (up to 21 days in saline solution), and allow the immobilization of gelatin (Gel) to further improve bioactivity. In vitro mineralization of the corresponding 3D conductive scaffolds was greatly enhanced (GOPS(NaOH)-Gel - 3.1 fold, DVS(NaOH)-Gel - 2.0 fold) and cell colonization and proliferation were the highest for the DVS(NaOH)-Gel scaffold. In silico modelling of ES application in DVS(NaOH)-Gel scaffolds indicates that the electrical field distribution is homogeneous, which reduces the probability of formation of faradaic products. Osteogenic differentiation of human bone marrow derived mesenchymal stem/stromal cells (hBM-MSCs) was performed under ES. Importantly, our results clearly demonstrated a synergistic effect of scaffold electroconductivity and ES on the enhancement of MSC osteogenic differentiation, particularly on cell-secreted calcium deposition and the upregulation of osteogenic gene markers such as COL I, OC and CACNA1C. These scaffolds hold promise for future clinical applications, including manufacturing of personalized bone TE grafts for transplantation with enhanced maturation/functionality or bioelectronic devices.

Biomaterials and Cell Therapy Combination in Central Nervous System Treatments.

Current pharmacological and surgical therapies for the central nervous system (CNS) show a limited capacity to reduce the damage progression; that together with the intrinsic limited capability of the CNS to regenerate greatly reduces the hopes of recovery. Among all the therapies proposed, the tissue engineering strategies supplemented with therapeutic stem cells remain the most promising. Neural tissue engineering strategies are based on the development of devices presenting optimal physical, chemical, and mechanical properties which, once inserted in the injured site, can support therapeutic cells, limiting the effect of a hostile environment and supporting regenerative processes. Thus, this review focuses on the employment of hydrogel and nanofibrous scaffolds supplemented with stem cells as promising therapeutic tools for the central and peripheral nervous systems in preclinical and clinical applications.

Structural and Molecular Changes of Human Chondrocytes Exposed to the Rotating Wall Vessel Bioreactor.

Over the last 30 years, the prevalence of osteoarthritis (OA), a disease characterized by a loss of articular cartilage, has more than doubled worldwide. Patients suffer from pain and progressive loss of joint function. Cartilage is an avascular tissue mostly consisting of extracellular matrix with embedded chondrocytes. As such, it does not regenerate naturally, which makes an early onset of OA prevention and treatment a necessity to sustain the patients' quality of life. In recent years, tissue engineering strategies for the regeneration of cartilage lesions have gained more and more momentum. In this study, we aimed to investigate the scaffold-free 3D cartilage tissue formation under simulated microgravity in the NASA-developed rotating wall vessel (RWV) bioreactor. For this purpose, we cultured both primary human chondrocytes as well as cells from the immortalized line C28/I2 for up to 14 days on the RWV and analyzed tissue morphology, development of apoptosis, and expression of cartilage-specific proteins and genes by histological staining, TUNEL-assays, immunohistochemical detection of collagen species, and quantitative real-time PCR, respectively. We observed spheroid formation in both cell types starting on day 3. After 14 days, constructs from C28/I2 cells had diameters of up to 5 mm, while primary chondrocyte spheroids were slightly smaller with 3 mm. Further inspection of the 14-day-old C28/I2 spheroids revealed a characteristic cartilage morphology with collagen-type 1, -type 2, and -type 10 positivity. Interestingly, these tissues were less susceptible to RWV-induced differential gene expression than those formed from primary chondrocytes, which showed significant changes in the regulation of IL6, ACTB, TUBB, VIM, COL1A1, COL10A1, MMP1, MMP3, MMP13, ITGB1, LAMA1, RUNX3, SOX9, and CASP3 gene expression. These diverging findings might reflect the differences between primary and immortalized cells. Taken together, this study shows that simulated microgravity using the RWV bioreactor is suitable to engineer dense 3D cartilage-like tissue without addition of scaffolds or any other artificial materials. Both primary articular cells and the stable chondrocyte cell line C28/I2 formed 3D neocartilage when exposed for 14 days to an RWV.

JANUS: an open-source 3D printable perfusion bioreactor and numerical model-based design strategy for tissue engineering.

Bioreactors have been employed in tissue engineering to sustain longer and larger cell cultures, managing nutrient transfer and waste removal. Multiple designs have been developed, integrating sensor and stimulation technologies to improve cellular responses, such as proliferation and differentiation. The variability in bioreactor design, stimulation protocols, and cell culture conditions hampered comparison and replicability, possibly hiding biological evidence. This work proposes an open-source 3D printable design for a perfusion bioreactor and a numerical model-driven protocol development strategy for improved cell culture control. This bioreactor can simultaneously deliver capacitive-coupled electric field and fluid-induced shear stress stimulation, both stimulation systems were validated experimentally and in agreement with numerical predictions. A preliminary in vitro validation confirmed the suitability of the developed bioreactor to sustain viable cell cultures. The outputs from this strategy, physical and virtual, are openly available and can be used to improve comparison, replicability, and control in tissue engineering applications.

Generation of highly pure pluripotent stem cell-derived myogenic progenitor cells and myotubes

Driving efficient and pure skeletal muscle cell differentiation from pluripotent stem cells (PSCs) has been challenging. Here, we report an optimized protocol that generates skeletal muscle progenitor cells with high efficiency and purity in a short period of time. Human induced PSCs (hiPSCs) and murine embryonic stem cells (mESCs) were specified into the mesodermal myogenic fate using distinct and species-specific protocols. We used a specific maturation medium to promote the terminal differentiation of both human and mouse myoblast populations, and generated myotubes associated with a large pool of cell-cycle arrested PAX7+ cells. We also show that myotube maturation is modulated by dish-coating properties, cell density, and percentage of myogenic progenitor cells. Given the high efficiency in the generation of myogenic progenitors and differentiated myofibers, this protocol provides an attractive strategy for tissue engineering, modeling of muscle dystrophies, and evaluation of new therapeutic approaches invitro.

Simulating 3D printing on hydrogel inks: A finite element framework for predicting mechanical properties and scaffold deformation

BackgroundDifficulties during the wound healing process may result in scarring, chronic wounds and sepsis. A common tissue engineering strategy to solve these problems rely on the development of 3D hydrogel scaffolds that mimic the structure, stiffness, and biological proprieties of the target tissue. One of the most effective biofabrication techniques to precisely control spatial deposition, architecture and porosity of hydrogels is 3D printing technology. However, final architectures of 3D printed structures can be compromised if the printing properties are not adequately selected. PurposeOur main goal was to create a numerical framework able to predict the deformations that arise due to the 3D printing process of hydrogel scaffolds. Our secondary goal was to analyze if the overall mechanical properties of the 3D printed scaffolds were affected by these deformations. MethodsWe applied finite element analysis using ABAQUS finite element software to develop our numerical framework. The finite elements were added in a time sequence, simulating the material deposition. The bulk material was experimentally characterized and represented numerically by the user-defined subroutine UMAT. We tested the simulation by ‘printing’ a 5.0 × 5.0 × 0.8 alginate ink at 5 and 10 mm/s. Afterwards, both the final 3D printed scaffolds and a theoretical non-deformed configuration were subjected to a uniaxial compression of 10 % of the initial height, and differences between their overall mechanical properties were analyzed. ResultsThe numerical framework captured the bending between the scaffold filaments and the compression of the bottom layers. On average, the scaffold printed at 5 mm/s deformed ∼6 % more, compared to the scaffold printed at 10 mm/s. However, in terms of overall mechanical properties, both showed similar behavior. This behavior, however, was highly nonlinear and significantly different from the theoretical, non-deformed scaffold, particularly in a small strains’ regime. ConclusionsA numerical framework that can be used as a preliminary tool to define the printing velocity, sequence and geometry, minimizing the deformations during the 3D printing process was developed. This framework can help to minimize experimentation and consequently, material waste. We also saw that these deformations should not be neglected when predicting the mechanical behavior using finite element analysis, particularly for small strains application.

Profiling joint tissues at single-cell resolution: advances and insights.

Advances in the profiling of human joint tissues at single-cell resolution have provided unique insights into the organization and function of these tissues in health and disease. Data generated by various single-cell technologies, including single-cell RNA sequencing and cytometry by time-of-flight, have identified the distinct subpopulations that constitute these tissues. These timely studies have provided the building blocks for the construction of single-cell atlases of joint tissues including cartilage, bone and synovium, leading to the identification of developmental trajectories, deciphering of crosstalk between cells and discovery of rare populations such as stem and progenitor cells. In addition, these studies have revealed unique pathogenetic populations that are potential therapeutic targets. The use of these approaches in synovial tissues has helped to identify how distinct cell subpopulations can orchestrate disease initiation and progression and be responsible for distinct pathological outcomes. Additionally, repair of tissues such as cartilage and meniscus remains an unmet medical need, and single-cell methodologies can be invaluable in providing a blueprint for both effective tissue-engineering strategies and therapeutic interventions for chronic joint diseases such as osteoarthritis and rheumatoid arthritis.

Priming chondrocytes during expansion alters cell behavior and improves matrix production in 3D culture

ObjectiveCartilage tissue engineering strategies that use autologous chondrocytes require in vitro expansion of cells to obtain enough cells to produce functional engineered tissue. However, chondrocytes dedifferentiate during expansion culture, limiting their ability to produce chondrogenic tissue and their utility for cell-based cartilage repair strategies. The current study identified conditions that favor cartilage production and the mechanobiological mechanisms responsible for these benefits. DesignChondrocytes were isolated from juvenile bovine knee joints and cultured with (primed) or without (unprimed) a growth factor cocktail. Gene expression, cell morphology, cell adhesion, cytoskeletal protein distribution, and cell mechanics were assessed. Following passage 5, cells were embedded into agarose hydrogels to evaluate functional properties of engineered cartilage. ResultsPriming cells during expansion culture altered cell phenotype and chondrogenic tissue production. Unbiased RNA-sequencing analysis suggested, and experimental studies confirmed, that growth factor priming delays dedifferentiation associated changes in cell adhesion and cytoskeletal organization. Priming also overrode mechanobiological pathways to prevent chondrocytes from remodeling their cytoskeleton to accommodate the stiff, monolayer microenvironment. Passage 1 primed cells deformed less and had lower YAP1 activity than unprimed cells. Differences in cell adhesion, morphology, and cell mechanics between primed and unprimed cells were mitigated by passage 5. ConclusionsPriming suppresses mechanobiologic cytoskeletal remodeling to prevent chondrocyte dedifferentiation, resulting in more cartilage-like tissue-engineered constructs

Strategies for Constructing Tissue-Engineered Fat for Soft Tissue Regeneration.

Repairing soft tissue defects caused by inflammation, tumors, and trauma remains a major challenge for surgeons. Adipose tissue engineering (ATE) provides a promising way to solve this problem. This review summarizes the current ATE strategies for soft tissue reconstruction, and introduces potential construction methods for ATE. Scaffold-based and scaffold-free strategies are the two main approaches in ATE. Although several of these methods have been effective clinically, both scaffold-based and scaffold-free strategies have limitations. The third strategy is a synergistic tissue engineering strategy and combines the advantages of scaffold-based and scaffold-free strategies. Personalized construction, stable survival of reconstructed tissues and functional recovery of organs are future goals of building tissue-engineered fat for ATE.

Extracellular matrix analysis of fibrosis: A step towards tissue engineering for urethral stricture disease.

The urogenital tract is a target for many congenital and acquired diseases, both benign and oncogenic. In males, the urethra that transports urine and semen can be obstructed by a fibrotic disease called urethral stricture disease (USD). In severe USD, the whole organ including the vascular embedding, the corpus spongiosum (CS), is affected. Recurrent or severe USD is treated by reconstructive surgery. Tissue engineering may improve the outcome of urethral reconstruction in patients with complicated USD. Currently in urethral reconstruction only the epithelial layer is replaced, no substitution for the CS is provided, while the CS is important for mechanical support and vascularization. To develop a tissue engineering strategy for the CS, it is necessary to know the protein composition of the CS. As the extracellular matrix (ECM) plays an important role in the formation of fibrosis, we analyzed the distribution and localization of ECM components in human healthy and fibrotic CS tissue using immunohistology. The morphology of components of the elastic network were affected in USD. After decellularization a clear enrichment of proteins belonging to the ECM was found. In the proteomic analysis collagens COL15A1 and COL4A2 as well as inter-alpha-trypsin inhibitor ITIH4 were upregulated in fibrotic samples. The glycoproteins Periostin (POSTN), Microfibrillar-associated protein 5 (MFAP5) and EMILIN2 are downregulated in fibrotic tissue. To our knowledge this is the first proteomic study of ECM proteins of the CS in healthy and in USD. With these results a regenerating approach for tissue engineered CS can be developed, including relevant ECM proteins that reduce fibrosis and promote healthy healing in urethral reconstructive surgery.

Chitosan‐gelatin/hydroxyapatite‐based scaffold associated with mesenchymal stem cells differentiate into osteoblasts improves the surface of the bone lesion in mice C57BL/6J

AbstractExtensive injuries to bone tissue are still considered a significant clinical challenge; therefore, developing new bone tissue engineering (BTE) strategies is still necessary. This work aims to construct and characterize a chitosan‐gelatin/hydroxyapatite‐based (CG/H) scaffold to provide well‐design support for mesenchymal stem cell (MSC) growth and differentiation to osteoblasts. First, the CG/H scaffolds are construct by freeze‐drying. Then, scanning electron microscopy (SEM), Fourier transform infrared spectroscopy, x‐ray diffraction, water uptake, and degradation profiles evaluate the material's surface. In addition, the CG/H morphological, biochemical, and MSC adhesion processes and growth behavior are also assess, indicating reasonable adhesion rates to the surface, low material cytotoxicity, and excellent alkaline phosphatase activity compared to control on the cellular framework. Based on these results, we obtain a highly biocompatible scaffold and that can support osteoblast differentiation. Finally, the in vivo studies demonstrate the CG/H scaffold with MSC adhere is capable of differentiating into osteoblasts, and the application of this scaffold is able to significantly enhance the closure of the bone lesion. Therefore, the CG/H scaffold has potential clinical application for bone regeneration.

Preparation and in vitro evaluation of biological agents based on Zinc-laponite- curcumin incorporated in alginate hydrogel

Due to their outstanding structures and properties, three-dimensional (3D) hydrogels and nanoparticles have been widely studied and indicated a very high potential for medical, therapeutic, and diagnostic applications. However, hydrogels and nanoparticles systems have particular drawbacks that limit their widespread applications. In recent years, the incorporation of nanostructured systems into hydrogel has been developed as a novel way for the formation of new biomaterials with various functions to solve biomedical challenges. In this study, alginate-loaded Zinc- laponite—curcumin (Zn/La/Cur) nanocomposites were fabricated via ionic cross-linking. The prepared nanocomposite hydrogels were characterized via FTIR and FE-SEM. Moreover, energy dispersive x-ray spectroscopy (EDX) was used to study the elements of the Zn/La/Cur nanocomposite. The NIH3T3 fibroblast cell line was utilized for the MTT assay to determine the cell viability of the fabricated alginate-loaded Zn/La/Cur nanocomposites. MTT results demonstrated that there was no evidence of toxicity in the samples. These outcomes suggest that applying Al/Zn/La/Cur nanocomposite as a biological agent could be a novel tissue engineering strategy for treating soft tissue disorders.Graphical

BMP9 is a potent inducer of chondrogenesis, volumetric expansion and collagen type II accumulation in bovine auricular cartilage chondroprogenitors.

Reconstruction of the outer ear currently requires harvesting of cartilage from the posterior of the auricle or ribs leading to pain and donor site morbidity. An alternative source for auricular reconstruction is in vitro tissue engineered cartilage using stem/progenitor cells. Several candidate cell-types have been studied with tissue-specific auricular cartilage progenitor cells (AuCPC) of particular interest. Whilst chondrogenic differentiation of competent stem cells using growth factor TGFβ1 produces cartilage this tissue is frequently fibrocartilaginous and lacks the morphological features of hyaline cartilage. Recent work has shown that growth factor BMP9 is a potent chondrogenic and morphogenetic factor for articular cartilage progenitor cells, and we hypothesised that this property extends to cartilage-derived progenitors from other tissues. In this study we show monoclonal populations of AuCPCs from immature and mature bovine cartilage cultured with BMP9 produced cartilage pellets have 3-5-fold greater surface area in sections than those grown with TGFβ1. Increased volumetric growth using BMP9 was due to greater sGAG deposition in immature pellets and significantly greater collagen accumulation in both immature and mature progenitor pellets. Polarised light microscopy and immunohistochemical analyses revealed that the organisation of collagen fibrils within pellets is an important factor in the growth of pellets. Additionally, chondrocytes in BMP9 stimulated cell pellets had larger lacunae and were more evenly dispersed throughout the extracellular matrix. Interestingly, BMP9 tended to normalise the response of immature AuCPC monoclonal cell lines to differentiation cues whereas cells exhibited more variation under TGFβ1. In conclusion, BMP9 appears to be a potent inducer of chondrogenesis and volumetric growth for AuCPCs a property that can be exploited for tissue engineering strategies for reconstructive surgery though with the caveat of negligible elastin production following 21-day treatment with either growth factor.

Hydrothermal synthesis of valve metal Zr-doped titanate nanofibers for bone tissue engineering

Investigations are underway to identify novel biomaterials to improve strategies for bone tissue engineering. Hybrid nanomaterials have emerged as a viable class of biomaterials. Here, we report a facile, economical, optimized, and well-controlled hydrothermal method for synthesizing Zr-doped potassium titanate nanofibers with high purity. Upon morphological characterization, Zr-doping did not disrupt the parent crystal structure of potassium titanate, which showed huge potential for bone tissue engineering.

Engineered Decellularized Tendon Matrix Putty Preserves Native Tendon Bioactivity to Promote Cell Proliferation and Enthesis Repair

Rotator cuff tears are a common soft tissue injury that can significantly decrease function of the shoulder and cause severe pain. Despite progress in surgical technique, rotator cuff repairs (RCRs) do not always heal efficiently. Many failures occur at the bone-tendon interface as a result of poor healing capacity of the tendon and failure to regenerate the native histological anatomy of the enthesis. While allografts are commercially available, clinical use is limited as they do not stimulate tissue regeneration and are associated with a structural failure of up to 40% in re-tear cases. Novel tissue engineering strategies are being developed with promise, but most involve addition of cells and/or growth factors which extends the timeline for clinical translation. Thus, there exists a significant unmet clinical need for easily translatable surgical augmentation approaches that can improve healing in RCR. Here we describe the development of a decellularized tendon matrix (DTM) putty that preserves native tendon bioactivity using a novel processing technique. In vitro, DTM promoted proliferation of tenocytes and adipose-derived stem cells with an increase in expression-specific transcription factors seen during enthesis development, Scleraxis and Sox9. When placed in a rabbit model of a chronic rotator cuff tear, DTM improved histological tissue repair by promoting calcification at the bone-tendon interface more similar to the normal fibrocartilaginous enthesis. Taken together, these data indicate that the engineered DTM putty retains a pro-regenerative bioactivity that presents a promising translational strategy for improving healing at the enthesis.

Conductive 3D Ti3C2Tx MXene-Matrigel hydrogels promote proliferation and neuronal differentiation of neural stem cells

Neural stem cells (NSCs) transplantation has great potential in the field of central nervous system injury repair, but the limited differentiation efficiency of transplanted NSCs often affects the therapeutic effect. In this paper, we present a stable three-dimensional (3D) conductive hydrogel prepared by cross-linking MXenes to Matrigel hydrogel. Benefiting from 3D microporous network structure of hydrogel, the conductive hydrogel can provide an extracellular matrix-like substrate for NSCs growth. Moreover, with the addition of Ti3C2Tx MXenes, the composite has excellent electrical conductivity and biocompatibility. It is demonstrated that MXene-Matrigel hydrogels can effectively promote the proliferation and differentiation of NSCs. These findings provide experimental evidence for understanding the regulatory role of conductive hydrogels on NSCs and provides new strategies for neural tissue engineering.

GelMA-catechol coated FeHAp nanorods functionalized nanofibrous reinforced bio-instructive and mechanically robust composite hydrogel scaffold for bone tissue engineering

Critical bone defects complicate tissue graft-based surgeries, raising healthcare expenditures and underscoring scaffold-based tissue-engineering strategies to support bone reconstruction. Our study highlighted that the phase-compatible combination of inorganic nanorods, nanofibers, and hydrogels is promising for developing biomimetic and cell-instructive scaffolds since the bone matrix is a porous organic/inorganic composite. In brief, methacrylated gelatin (GelMA) was reacted with dopamine to form catechol-modified GeLMA (GelMA-C). The GelMA-C was nanocoated onto an iron-doped hydroxyapatite (FeHAp) nanorod via metal-catechol network coordination. The modified nanorod (FeHAp@GelMA-C) was loaded onto GelMA-based nanofibers. The nanorods loaded pre-fibers were electrospun onto GelMA solution and photochemically crosslinked to fabricate a fiber-reinforced hydrogel. The structural, mechanical, physicochemical, biocompatibility, swelling properties, osteogenic potential, and bone remodelling potential (using rat femoral defect model) of modified nanorods, simple hydrogel, and nanorod-loaded fiber-reinforced hydrogel were studied. The results supported that the interface interaction between GelMA-C/nanorods, nanorods/nanofibers, nanorods/hydrogels, and nanofiber/hydrogels significantly improved the microstructural and mechanical properties of the scaffold. Compared to pristine hydrogel, the nanorod-loaded fiber-reinforced scaffold better supported cellular responses, osteogenic differentiation, matrix mineralization, and accelerated bone regeneration. The nanorod-loaded fiber-reinforced hydrogel proved more biomimetic and cell-instructive for guided bone reconstruction.

Type 2 diabetes impairs annulus fibrosus fiber deformation and rotation under disc compression in the University of California Davis type 2 diabetes mellitus (UCD-T2DM) rat model

Abstract Understanding the biomechanical behavior of the intervertebral disc is crucial for studying disease mechanisms and developing tissue engineering strategies for managing disc degeneration. We used synchrotron small-angle X-ray scattering to investigate how changes to collagen behavior contribute to alterations in the disc’s ability to resist compression. Coccygeal motion segments from 6-month-old lean Sprague-Dawley rats ( n=7) and diabetic obese University of California Davis type 2 diabetes mellitus (UCD-T2DM) rats ( n=6, diabetic for 68±7 days) were compressed during simultaneous synchrotron scanning to measure collagen strain at the nanoscale (beamline 7.3.3 of the Advanced Light Source). After compression, the annulus fibrosus was assayed for nonenzymatic cross-links. In discs from lean rats, resistance to compression involved two main energy-dissipation mechanisms at the nanoscale: (1) rotation of the two groups of collagen fibrils forming the annulus fibrosus and (2) straightening (uncrimping) and stretching of the collagen fibrils. In discs from diabetic rats, both mechanisms were significantly impaired. Specifically, diabetes reduced fibril rotation by 31% and reduced collagen fibril strain by 30% (compared to lean discs). The stiffening of collagen fibrils in the discs from diabetic rats was consistent with a 31% higher concentration of nonenzymatic cross-links and with evidence of earlier onset plastic deformations such as fibril sliding and fibril–matrix delamination. These findings suggest that fibril reorientation, stretching, and straightening are key deformation mechanisms that facilitate whole-disc compression, and that type 2 diabetes impairs these efficient and low-energy elastic deformation mechanisms, thereby altering whole-disc behavior and inducing the earlier onset of plastic deformation.