Mineralized Collagen Fibrils Research Articles

Three dimensional structures of the inner and outer pig petrous bone using FIB-SEM: Implications for development and ancient DNA preservation

We report on the 3D ultrastructure of the mineralized petrous bone of mature pig using focused ion beam – scanning electron microscopy (FIB-SEM). We divide the petrous bone into two zones based on the degree of mineralization; one zone close to the otic chamber has higher mineral density than the second zone further away from the otic chamber. The hypermineralization of the petrous bone results in the collagen D-banding being poorly revealed in the lower mineral density zone (LMD), and absent in the high mineral density zone (HMD). We therefore could not use D-banding to decipher the 3D structure of the collagen assembly. Instead we exploited the anisotropy option in the Dragonfly image processing software to visualize the less mineralized collagen fibrils and/or nanopores that surround the more mineralized zones known as tesselles. This approach therefore indirectly tracks the orientations of the collagen fibrils in the matrix itself. We show that the HMD bone has a structure similar to that of woven bone, and the LMD is composed of lamellar bone with a plywood-like structural motif. This agrees with the fact that the bone close to the otic chamber is fetal bone and is not remodeled. The lamellar structure of the bone further away from the otic chamber is consistent with modeling/remodeling. The absence of the less mineralized collagen fibrils and nanopores resulting from the confluence of the mineral tesselles may contribute to shielding DNA during diagenesis. We show that anisotropy evaluation of the less mineralized collagen fibrils could be a useful tool to analyze bone ultrastructures and in particular the directionality of collagen fibril bundles that make up the bone matrix.

A 3D Cell‐Free Bone Model Shows Collagen Mineralization is Driven and Controlled by the Matrix

AbstractOsteons, the main organizational components of human compact bone, are cylindrical structures composed of layers of mineralized collagen fibrils, called lamellae. These lamellae have different orientations, different degrees of organization, and different degrees of mineralization where the intrafibrillar and extrafibrillar minerals are intergrown into one continuous network of oriented crystals. While cellular activity is clearly the source of the organic matrix, recent in vitro studies call into question whether the cells are also involved in matrix mineralization and suggest that this process could be simply driven by the interactions of the mineral with extracellular matrix. Through the remineralization of demineralized bone matrix, the complete multiscale reconstruction of the 3D structure and composition of the osteon without cellular involvement are demonstrated. Then, this cell‐free in vitro system is explored as a realistic, functional model for the in situ investigation of matrix‐controlled mineralization processes. Combined Raman and electron microscopy indicate that glycosaminoglycans (GAGs) play a more prominent role than generally assumed in the matrix–mineral interactions. The experiments also show that the organization of the collagen is in part a result of its interaction with the developing mineral.

3D Tortuosity and Diffusion Characterization in the Human Mineralized Collagen Fibril Using a Random Walk Model.

Bone tissue is mainly composed at the nanoscale of apatite minerals, collagen molecules and water that form the mineralized collagen fibril (MCF). In this work, we developed a 3D random walk model to investigate the influence of bone nanostructure on water diffusion. We computed 1000 random walk trajectories of water molecules within the MCF geometric model. An important parameter to analyse transport behaviour in porous media is tortuosity, computed as the ratio between the effective path length and the straight-line distance between initial and final points. The diffusion coefficient is determined from the linear fit of the mean squared displacement of water molecules as a function of time. To achieve more insight into the diffusion phenomenon within MCF, we estimated the tortuosity and diffusivity at different quotes in the longitudinal direction of the model. Tortuosity is characterized by increasing values in the longitudinal direction. As expected, the diffusion coefficient decreases as tortuosity increases. Diffusivity outcomes confirm the findings achieved by experimental investigations. The computational model provides insights into the relation between the MCF structure and mass transport behaviour that may contribute to the improvement of bone-mimicking scaffolds.

Mineralized Collagen Fibrils: An Essential Component in Determining the Mechanical Behavior of Cortical Bone

Bone comprises mechanically different materials in a specific hierarchical structure. Mineralized collagen fibrils (MCFs), represented by tropocollagen molecules and hydroxyapatite nanocrystals, are the fundamental unit of bone. The mechanical characterization of MCFs provides the unique adaptive mechanical competence to bone to withstand mechanical load. The structural and mechanical role of MCFs is critical in the deformation mechanisms of bone and the marvelous strength and toughness possessed by bone. However, the role of MCFs in the mechanical behavior of bone across multiple length scales is not fully understood. In the present study, we shed light upon the latest progress regarding bone deformation at multiple hierarchical levels and emphasize the role of MCFs during bone deformation. We propose the concept of hierarchical deformation of bone to describe the interconnected deformation process across multiple length scales of bone under mechanical loading. Furthermore, how the deterioration of bone caused by aging and diseases impairs the hierarchical deformation process of the cortical bone is discussed. The present work expects to provide insights on the characterization of MCFs in the mechanical properties of bone and lays the framework for the understanding of the multiscale deformation mechanics of bone.

Competing mechanisms in fracture of staggered mineralized collagen fibril arrays

Mineralized collagen fibril (MCF) arrays are important structural elements involved in inelastic deformation and fracture process of bone. Recent experiments have shown that MCF breakage has an influence on toughening of bone. Motivated by the experiments, we carry out the analyses of fracture in staggered MCF arrays. The plastic deformation of extrafibrillar matrix (EFM), debonding of the MCF-EFM interface, plastic deformation of MCFs and MCF fracture are accounted for in the calculations. It is found that the fracture of MCF arrays is controlled by competition between MCF breakage and debonding of the MCF-EFM interface. The MCF-EFM interface with high shear strength and large shear fracture energy is capable of activating MCF breakage, which promotes plastic energy dissipation of MCF arrays. In the absence of MCF breakage, damage energy dissipation is higher than plastic energy dissipation and debonding of the MCF-EFM interface provides the major contribution to toughening of bone. We have further revealed that the relative contributions of interfacial debonding mechanism and plastic deformation of MCF arrays are dependent on fracture properties of the MCF-EFM interface in the normal direction. The high normal strength gives rise to enhanced damage energy dissipation and amplified plastic deformation of MCF arrays; while high normal fracture energy of the interface suppresses plastic deformation of MCFs.

Biomimetic mineralized collagen scaffolds enhancing odontogenic differentiation of hDPSCs and dentin regeneration through modulating mechanical microenvironment

Dentin regeneration is a huge challenge because of its complicated structure and the shortage of odontoblasts. Unlike in vitro remineralization of dentin through supersaturation of calcium phosphate, the materials of mineralized collagen scaffolds could recruit the human dental pulp stem cells (hDPSCs) and induce their differentiation in vivo and achieve dentin repair. Inspired by the biomineralization of dentin, herein, mineralized collagen fibrils with various mineralization degrees and mechanical properties were prepared through biomolecule hyaluronic acid (HA) modification, and first time find the mechanical properties have a positive correlation with mineralization degree. When 1.2 mg/mL HA was used to modification, the mineralized HA-modified collagen scaffolds (HA-MCS) with similar modulus and stiffness to that of natural dentin could be obtained. Furthermore, testing ALP activity and alizarin red S staining experiments confirmed the HA-MCS with a biomimetic mechanical microenvironment could enhance the proliferation and differentiation of hDPSCs. Additionally, in vivo experiments performed on the beagle model further proved this point that HA-MCS with a biomimetic mechanical microenvironment could promote dentin regeneration. These results not only elucidate that the modulation of mechanical properties of biomaterials could enhance the proliferation and differentiation of stem cells, but also provide a strategy for hard tissue regeneration.

Investigating the post-yield behavior of mineralized bone fibril arrays using a 3D non-linear finite element unit-cell model

In this study, we propose a 3D non-linear finite element (FE) unit-cell model to investigate the post-yield behavior of mineralized collagen fibril arrays (FAY). We then compare the predictions of the model with recent micro-tensile and micropillar compression tests in both axial and transverse directions. The unit cell consists of mineralized collagen fibrils (MCFs) embedded in an extrafibrillar matrix (EFM), and the FE mesh is equipped with cohesive interactions and a custom plasticity model. The simulation results confirm that MCF plays a dominant role in load bearing prior to yielding under axial tensile loading. Damage was initiated via debonding in shear and progressive sliding at the MCF/EFM interface, and resulted in MCF pull-out until brittle failure. In transverse tensile loading, EFM carried most of the load in pre-yield deformation, and then mixed normal/shear debonding between MCF and EFM began to form, which eventually produced brittle delamination of the two phases. The loading/unloading FE analysis in compression along both axial and transverse directions demonstrated perfect plasticity without any reduction in elastic modulus, i.e., damage due to the interfaces as seen in micropillar compression. Beyond the brittle and ductile nature of the stress–strain curves, in tensile and compressive loading, the simulated post-yield behavior and failure mechanism are in good quantitative agreement with the experimental observations. Our rather simple but efficient unit-cell FE model can reproduce qualitatively and quantitatively the mechanical behavior of bone ECM under tensile and compressive loading along the two main orientations. The model's integration into higher length scales may be useful in describing the macroscopic post-yield and failure behavior of trabecular and cortical bone in greater detail.

A coarse-grained molecular dynamics investigation of the role of mineral arrangement on the mechanical properties of mineralized collagen fibrils.

Mineralized collagen fibrils (MCFs) comprise collagen molecules and hydroxyapatite (HAp) crystals and are considered universal building blocks of bone tissue, across different bone types and species. In this study, we developed a coarse-grained molecular dynamics (CGMD) framework to investigate the role of mineral arrangement on the load-deformation behaviour of MCFs. Despite the common belief that the collagen molecules are responsible for flexibility and HAp minerals are responsible for stiffness, our results showed that the mineral phase was responsible for limiting collagen sliding in the large deformation regime, which helped the collagen molecules themselves undergo high tensile loading, providing a substantial contribution to the ultimate tensile strength of MCFs. This study also highlights different roles for the mineralized and non-mineralized protofibrils within the MCF, with the mineralized groups being primarily responsible for load carrying due to the presence of the mineral phase, while the non-mineralized groups are responsible for crack deflection. These results provide novel insight into the load-deformation behaviour of MCFs and highlight the intricate role that both collagen and mineral components have in dictating higher scale bone biomechanics.

Hierarchically Engineered Artificial Lamellar Bone with High Strength and Toughness

Complex hierarchical architectures are ubiquitous in natural hard tissues, which comprise an elaborate assembly of hard and soft phases spanning from the nanoscale to the macroscale. The elegant architectures grant unique performance in terms of strength and toughness, but the biomimetic fabrication of synthetic materials with highly consistent structural and mechanical characteristics with natural counterparts remains a great challenge. Here, a centimeter‐size artificial lamellar bone is successfully fabricated for the first time via a well‐orchestrated “multiscale cascade regulation” strategy combining multiple techniques of molecular self‐assembly, electrospinning, and pressure‐driven fusion from molecular to macroscopic levels. The bulk artificial lamellar bone that is composed of hierarchically assembled mineralized collagen fibrils with a waiver of any synthetic polymer highly resembles the chemical composition, multiscale structural organization, and rotated plywood‐like structure of natural lamellae, thus achieving a good combination of lightweight and high‐stiffness (Ey ≈ 15.2 GPa), ‐strength (σf ≈ 118.4 MPa), and ‐toughness (KJC ≈ 9.3 MPa m1/2). This multiscale cascade regulation strategy can break through the limitations of a single technique and enable the construction of elaborate composite materials with multiscale step‐by‐step regulations of hierarchically structural organizations for unique mechanical properties.

Aging exacerbates the morphological and mechanical response of mineralized collagen fibrils in murine cortical bone to disuse

Mineralized collagen fibrils (MCFs) are the fundamental building blocks of bone tissue and contribute significantly to the mechanical behavior of bone. However, it is still largely unknown how the collagen network in bone responds to aging and the disuse normally accompanying it. Utilizing atomic force microscopy, nanoindentation and Raman spectroscopy, age-related alterations in the microstructure and mechanical properties of murine cortical tibia at multiple scales were investigated in this study. The potential difference in the responses of bone to disuse at different ages was studied. The results indicated that the age- and disuse-related alterations in bone initiate from MCFs in the bone matrix. The D-periodic spacing, radial elastic modulus of a single MCF and the mineral-to-matrix ratio on the cortical bone surface were larger in aged mice than in adult mice. Disuse, on the other hand, mainly has a major influence on aged mice, particularly on the morphology and mechanical properties of MCFs, but it only has modest effects on adult bone. These findings revealed insights into the morphological and mechanical adaptation of mineralized collagen fibrils in murine cortical bone to aging and disuse. Statement of significanceBone is a complex structured composite material consisting of an interwoven framework of collagen fibrils reinforced by mineral particles and embedded in an extrafibrillar mineralized matrix. Utilizing atomic force microscopy, nanoindentation and Raman spectroscopy, this study suggests that the effects of aging, as well as the accompanying disuse, on the morphology and mechanical properties of bone initiate from the mineralized collagen fibril level. More interestingly, the MCF in the bone of aged mice seems to be more sensitive to disuse than that in adult mice. These findings significantly further the current understanding of the adaptation process of bone to aging at the mineralized collagen fibril level and provide direct insights into the physiological response of bone to aging and the abnormal mechanical environment.

Amyloid-like oligomeric nanospheres modify type I collagen to promote intrafibrillar mineralization

Mineralized collagen fibrils are the basic building block of bone, dentin and cementum. Great efforts have been made to achieve biomimetic mineralization of collagen fibrils in vitro to treat hard tissue damage, but there is a key challenge to obtain remineralized collagen with mineral contents and mechanical properties comparable to those of natural hard tissues. Meanwhile, the low efficiency and time-consuming period of mineralization should not be neglected. Therefore, we propose a novel strategy of biomimetic collagen mineralization that uses biocompatible and versatile amyloid-like oligomeric nanospheres (ALONs) to modify and cross-link collagen fibrils to promote intrafibrillar collagen mineralization. ALONs can adhere to collagen fibrils, and the inherent abundant functional groups of ALONs attract calcium ions and phosphate ions to form the ALONs-CaP complex, which increases the pool of mineralization precursors available for intrafibrillar mineralization. Higher-quality mineralized collagen with better biomechanical properties is achieved in 3 h compared with mineralization of unmodified collagen. The ALONs-CaP complex may provide a new collagen mineralization strategy to promote intrafibrillar mineralization and serve as a reference for understanding the mechanism of intrafibrillar mineralization.

Numerical modelling of cancellous bone damage using an orthotropic failure criterion and tissue elastic properties as a function of the mineral content and microporosity

Background and objective: Elastic and strength properties of lamellar tissue are essential to analyze the mechanical behaviour of bone at the meso- or macro-scale. Although many efforts have been made to model the architecture of cancellous bone, in general, isotropic elastic constants are assumed for tissue modelling, neglecting its non-isotropic behaviour. Therefore, isotropic damage laws are often used to estimate the bone failure. The main goals of this work are: (1) to present a new model for the estimation of the elastic properties of lamellar tissue which includes the bone mineral density (BMD) and the microporosity, (2) to address the numerical modelling of cancellous bone damage using an orthotropic failure criterion and a discrete damage mechanics analysis, including the novel approach for the tissue elastic properties aforementioned.Methods: Numerical homogenization has been used to estimate the elastic properties of lamellar bone considering BMD and microporosity. Microcomputed Tomography (μ-CT) scans have been performed to obtain the micro-finite element (μ-FE) model of cancellous bone from a vertebra of swine. In this model, lamellar tissue is orientated by considering a unidirectional layer pattern being the mineralized collagen fibrils aligned with the most representative geometrical feature of the trabeculae network. We have considered the Hashin’s failure criterion and the Material Property Degradation (MPDG) method for simulating the onset and evolution of bone damage.Results: The terms of the stiffness matrix for lamellar tissue are derived as functions of the BMD and microporosity at tissue scale. Results obtained for the apparent yield strain values agree with experimental values found in the literature. The influence of the damage parameters on the bone mechanics behaviour is also presented.Conclusions: Stiffness matrix of lamellar tissue depends on both BMD and microporosity. The new approach presented in this work enables to analyze the influence of the BMD and porosity on the mechanical response of bone. Lamellar tissue orientation has to be considered in the mechanical analysis of the cancellous bone. An orthotropic failure criterion can be used to analyze the bone failure onset instead of isotropic criteria. The elastic property degradation method is an efficient procedure to analyze the failure propagation in a 3D numerical model.

Devising Bone Molecular Models at the Nanoscale: From Usual Mineralized Collagen Fibrils to the First Bone Fibers Including Hydroxyapatite in the Extra-Fibrillar Volume.

At the molecular scale, bone is mainly constituted of type-I collagen, hydroxyapatite, and water. Different fractions of these constituents compose different composite materials that exhibit different mechanical properties at the nanoscale, where the bone is characterized as a fiber, i.e., a bundle of mineralized collagen fibrils surrounded by water and hydroxyapatite in the extra-fibrillar volume. The literature presents only models that resemble mineralized collagen fibrils, including hydroxyapatite in the intra-fibrillar volume only, and lacks a detailed prescription on how to devise such models. Here, we present all-atom bone molecular models at the nanoscale, which, differently from previous bone models, include hydroxyapatite both in the intra-fibrillar volume and in the extra-fibrillar volume, resembling fibers in bones. Our main goal is to provide a detailed prescription on how to devise such models with different fractions of the constituents, and for that reason, we have made step-by-step scripts and files for reproducing these models available. To validate the models, we assessed their elastic properties by performing molecular dynamics simulations that resemble tensile tests, and compared the computed values against the literature (both experimental and computational results). Our results corroborate previous findings, as Young’s Modulus values increase with higher fractions of hydroxyapatite, revealing all-atom bone models that include hydroxyapatite in both the intra-fibrillar volume and in the extra-fibrillar volume as a path towards realistic bone modeling at the nanoscale.

A multiscale finite element investigation on the role of intra- and extra-fibrillar mineralisation on the elastic properties of bone tissue

Lamellar bone is one of the fundamental structural units of bone tissue and it consists of mineralised collagen fibrils (MCFs) embedded within an extra-fibrillar matrix comprised of hydroxyapatite minerals distributed throughout a matrix of non-collagenous proteins (NCPs). While both intra- and extra-fibrillar phases provide a critical contribution to tissue-level behaviour, the mechanical implications of their structural arrangement, and in particular the relative distribution of HA minerals between both phases, remains poorly understood. This study presents a multiscale finite element framework to investigate the role of intra- and extra-fibrillar mineralisation on the elastic properties of bone tissue by considering two levels of structural hierarchy. At the nanoscale, representative volume elements (RVEs) of both MCFs and the extra-fibrillar matrix were developed, and a homogenisation strategy was used to determine the effective elastic properties of each phase. At the sub-micron level, an RVE of lamellar bone that accounted for newly reported patterns of mineral platelets encircling collagen fibrils was used to predict the effective response of lamellar bone tissue, with material properties established from the previous length scale. The results demonstrated that the overall mineral content in the tissue is the biggest contributor to the effective elastic properties of lamellar bone. While this is perhaps unsurprising, importantly, it was demonstrated that the extra-fibrillar matrix (and mineral therein) is the phase that makes the primary contribution to the elastic response of the tissue. The two main reasons that the extra-fibrillar matrix dominated the load-bearing response are (i) the greater proportion of mineral content compared to the intra-fibrillar regions and (ii) the highly ordered arrangement of mineral platelets that are aligned to the longitudinal axis of MCFs. Both of these features resulted in extra-fibrillar mineral strain ratios that were consistently higher than intra-fibrillar mineral strain ratios under axial loading. As a result, the predicted elastic properties of MCFs were much lower than the extra-fibrillar matrix, indicating that intra-fibrillar mineralisation only provided a modest contribution to the stiffness of bone tissue. Collectively, the predicted results of the multiscale approach compared well to the range properties measured through various experimental testing methods, highlighting its potential to provide further insight into the role of sub-tissue features of tissue biomechanics.

C-Axis-Oriented Platelets of Crystalline Hydroxyapatite in Biomimetic Intrafibrillar Mineralization of Polydopamine-Functionalized Collagen Type I.

Mineralized collagen fibrils are important basic building blocks of calcified tissues, such as bone and dentin. Polydopamine (PDA) can introduce functional groups, i.e., hydroxyl and amine groups, on the surfaces of type I collagen (Col-I) as possible nucleation sites of calcium phosphate (CaP) crystallization. Molecular bindings in between PDA and Col-I fibrils (Col-PDA) have been found to significantly reduce the interfacial energy. The wetting effect, mainly hydrophilicity due to the functional groups, escalates the degree of mineralization. The assembly of Col-I molecules into fibrils was initiated at the designated number of collagenous molecules and PDA. In contrast to the infiltration of amorphous calcium phosphate (ACP) precursors into the Col-I matrix by polyaspartic acid (pAsp), this collagen assembly process allows nucleation and ACP to exist in advance by PDA in the intrafibrillar matrix. PDA bound to specific sites, i.e., gap and overlap zones, by the regular arrangement of Col-I fibrils enhanced ACP nucleation and thus mineralization. As a result, the c-axis-oriented platelets of crystalline hydroxyapatite in the Col-I fibril matrix were observed in the enhanced mineralization through PDA functionalization.

Ultrasound-assisted solubilization of calcium from micrometer-scale ground fish bone particles.

In order to promote the extraction of biological calcium from fish bone, ultrasonication was used to process micrometer‐scale fish bone particles (MFPs) and investigate the mechanism of action in relation to bone structure. With ultrasonication treatment (300 W, 60°C, 2 h), the content of calcium release increased by 25.6%. Calcium release reached 94.0% of total calcium after 24‐h treatment. The surface of the MFPs was significantly damaged by ultrasound‐induced cavitation, resulting in holes and separation of the layered structure. X‐ray diffraction (XRD) and Fourier transform infrared (FT‐IR) analysis demonstrated that the crystalline structure of hydroxyapatite was disrupted, the triple helical structure of mineralized collagen fibrils (MCFs) was loosened, and hydrogen bonding in collagen decreased, facilitating the release of hydroxyapatite crystals. Thus, ultrasonication may be a practical alternative to nanomilling for industrial processing of waste fish bones to produce soluble calcium as an ingredient in calcium supplements and supplemented foods.

A nanostructured look of collagen apatite porosity into human mineralized collagen fibril

Bone tissue is a hierarchical material characterized at nanoscale by the mineralized collagen fibril, a recurring structure mainly composed of apatite minerals, collagen and water. Bone nanostructure has a fundamental role in determining the mechanical behavior of the tissue and its mass transport properties. Diffusion phenomenon allows to maintain an adequate supply of metabolites in the mechanisms of bone remodeling, adaptation and repair. Several analytical and computational models have been developed to analyze and predict bone tissue behavior. However, the fine replication of the natural tissue still represents a challenge. Insights on the structural organization at nanoscale and on the influence of apatite mineral crystals on the diffusion coefficient lead to outline the functional conditions for the development of biomimetic strategies for bone tissue engineering. Thorough understanding of bone nanostructure is essential to improve longevity of bioscaffolds and to decrease the risk of failure by controlling their mechanical and biological performance.

Aging Exacerbates the Morphological and Mechanical Response of Mineralized Collagen Fibrils in Murine Cortical Bone to Disuse

Aging Exacerbates the Morphological and Mechanical Response of Mineralized Collagen Fibrils in Murine Cortical Bone to Disuse

Removal of glycosaminoglycans affects the in situ mechanical behavior of extrafibrillar matrix in bone

Previous studies have shown that glycosaminoglycans (GAGs) in bone matrix, coupling with water in bone matrix, may play a significant role in toughening bone tissues. Since GAGs are most likely present only in the extrafibrillar matrix (EFM) of bone, we hypothesized that GAGs in EFM would have a major impact on bone tissue toughness. To confirm this conjecture, we removed GAGs ex vivo from human cadaveric bone samples using a protein deglycosylation mix kit and then examined the in situ mechanical behavior of mineralized collagen fibrils (MCFs) and the surrounding EFM of the samples, using a high-resolution atomic force microscopy (AFM). By testing the bone samples before and after removal of GAGs, we found that under the wet condition removal of GAGs resulted in an increase in the elastic modulus of both EFM and MCFs, whereas a significant decrease in plastic energy dissipation was observed mainly in EFM. In contrast, under the dry condition the removal of GAGs had little effects on the mechanical properties of either MCFs or EFM. These results suggest that both MCFs and EFM contribute to the plastic energy dissipation of bone, whereas in the presence of matrix water removal of GAGs significantly reduces the capacity of EFM in plastic energy dissipation, but not MCFs. In addition, GAGs may affect the elastic modulus of both EFM and MCFs. These findings give rise to new understanding to the underlying mechanism of GAGs in toughening of bone tissues.

Oriented Strontium Carbonate Nanocrystals within Collagen Films for Flexible Piezoelectric Sensors

AbstractBone, assembled by mineralized collagen fibrils, displays piezoelectric properties under external stimulation to affect tissue growth. The mineralized collagen fibrils consist of collagen and oriented inorganic nanocrystals. Inspired from the unique structures and piezoelectric effect of mineralized collagen fibrils, the intrafibrillar mineralization of oriented strontium carbonate nanocrystals is achieved in vitro, which also exhibits good piezoelectric properties. The amorphous strontium carbonate precursors penetrate from the gap zones and fill gradually into the whole space within the collagen fibrils, and transform into a co‐oriented crystalline phase. Isolated mineralized collagen fibrils with organized SrCO3 nanocrystals acquire good flexible properties and inverse piezoelectric responses with an effective piezoelectric coefficient of 3.45 pm V−1, much higher than individual collagen (1.12 pm V−1) and SrCO3 crystals (0.092 pm V−1). These results may indicate that the organic and inorganic components synergistically contribute to the piezoelectric effect of bone. Furthermore, devices of flexible piezoelectric thin films assembled by SrCO3 mineralized collagen fibrils exhibit a regular open‐circuit voltage of 1.2 V under compressive stress and a stable cycling short‐circuit current of 80 nA under a bending mode. It can also facilitate the development of promising piezoelectric sensors.