Collagen-based Biomaterials Research Articles

Collagen-based biomaterials for biomedical applications.

Collagen is an insoluble fibrous protein that composes the extracellular matrix in animals. Although collagen has been used as a biomaterial since 1881, the properties and the complex structure of collagen are still extensive study subjects worldwide. In this article, several topics of importance for understanding collagen research are reviewed starting from its historical milestones, followed by the description of the collagen superfamily and its complex structures, with a focus on type I collagen. Subsequently, some of the superior properties of collagen-based biomaterials, such as biocompatibility, biodegradability, mechanical properties, and cell activities, are pinpointed. These properties make collagen applicable in biomedicine, such as wound healing, tissue engineering, surface coating of medical devices, and skin supplementation. Moreover, some antimicrobial strategies and the general host tissue responses regarding collagen as a biomaterial are presented. Finally, the current status and clinical application of the three-dimensional (3D) printing techniques for the fabrication of collagen-based scaffolds and the reconstruction of the human heart's constituents, such as capillary structures or even the entire organ, are discussed. Besides, an overall outlook for the future of this unique biomaterial is provided.

Determination of glycosaminoglycans in biological matrices using a simple and sensitive reversed-phase HPLC method with fluorescent detection

This paper suggests a sensitive reversed-phase gradient HPLC method combined with fluorescence detection that has been developed, optimized and tested via the quantitative analysis of authentic biological material in an effort to determine and subsequently compare the total content of glycosaminoglycans (GAGs) in various collagen-based biomaterials intended for medical application.The proposed analytical method enabled the identification and separation of the GAGs present from the other components in the samples using commonly-available laboratory equipment; moreover, the very low detection limit of the method permits the determination of GAGs even for very small samples.This study describes the development of the method, including the isolation and processing of the collagen samples prior to HPLC analysis and the optimal parameters applied during the chromatographic analysis. The application of the method in laboratory practice is documented by means of several examples of the determination of GAGs employing both commercial standards and real collagen samples isolated from various animal tissues.

The Role of Collagen-Based Biomaterials in Chronic Wound Healing and Sports Medicine Applications.

Advancements in tissue engineering have taken aim at treating tissue types that have difficulty healing naturally. In order to achieve improved healing conditions, the balance of exogenous matrix, cells, and different factors must be carefully controlled. This review seeks to explore the aspects of tissue engineering in specific tissue types treated in sports medicine and advanced wound management from the perspective of the matrix component. While the predominant material to be discussed is collagen I, it would be remiss not to mention its relation to the other contributing factors to tissue engineered healing. The main categories of materials summarized here are (1) reconstituted collagen scaffolds, (2) decellularized matrix tissue, and (3) non-decellularized tissue. These three groups are ordered by their increase in additional components beyond simply collagen.

Collagen nanomaterial in the recovery of motor ability of patients with peripheral nerve transection injury

Objective: The combination of neurotrophic factors and ordered collagen material can promote the regeneration of nerve fibres in the injured area, which has a good effect on the recovery of motor ability in patients with peripheral nerve transection. In this paper, the collagen composite scaffolds were used to repair peripheral nerve defects, and then the collagen scaffolds combined with neurotrophic factors were used to promote axon regeneration and motor function recovery in rats with total transection of peripheral nerve. The experimental results show that the fusion of neurotrophic factors with collagen binding domain can specifically bind to collagen-based biomaterials, prevent rapid diffusion of factors in vivo, thus maintaining a more uniform release efficiency in vivo, which can be widely used in the study of motor ability recovery of peripheral nerve transection patients.

Proteomic Analysis of Porcine-Derived Collagen Membrane and Matrix.

Collagen membranes and matrices being widely used in guided bone regeneration and soft tissue augmentation have characteristic properties based on their composition. The respective proteomic signatures have not been identified. Here, we performed a high-resolution shotgun proteomic analysis on two porcine collagen-based biomaterials designed for guided bone regeneration and soft tissue augmentation. Three lots each of a porcine-derived collagen membrane and a matrix derived from peritoneum and/or skin were digested and separated by nano-reverse-phase high-performance liquid chromatography. The peptides were subjected to mass spectrometric detection and analysis. A total of 37 proteins identified by two peptides were present in all collagen membranes and matrices, with 11 and 16 proteins being exclusively present in the membrane and matrix, respectively. The common extracellular matrix proteins include fibrillar collagens (COL1A1, COL1A2, COL2A1, COL3A1, COL5A1, COL5A2, COL5A3, COL11A2), non-fibrillar collagens (COL4A2, COL6A1, COL6A2, COL6A3, COL7A1, COL16A1, COL22A1), and leucine-rich repeat proteoglycans (DCN, LUM, BGN, PRELP, OGN). The structural proteins vimentin, actin-based microfilaments (ACTB), annexins (ANXA1, ANXA5), tubulins (TUBA1B, TUBB), and histones (H2A, H2B, H4) were also identified. Examples of membrane-only proteins are COL12A1 and COL14A1, and, of matrix only proteins, elastin (ELN). The proteomic signature thus revealed the similarities between but also some individual proteins of collagen membrane and matrix.

Nile Tilapia Fish Skin, Scales, and Spine as Naturally Derived Biomaterials for Tissue Regeneration

This study aims to review the literature on the use of Nile tilapia-derived extracellular matrix (ECM) proteins as naturally derived scaffold material for tissue regeneration. Nile tilapia has emerged as a particularly relevant specie for the development of fish-derived biomaterials. The skin, scale, and spine of various fish species have been extensively demonstrated as a potential source of native ECM proteins for use in regenerative medicine. When compared to synthetic polymers, collagen-based biomaterials introduce some disadvantages due to their lower biomechanical stiffness and rapid biodegradation. However, collagen-based biomaterials continue to be one of the most highly investigated natural materials for bone regeneration. Studies have pointed to tilapia as a satisfactory source of collagen for its quality and cost benefit, with good responses in vitro and in vivo, especially studies involving the skin as the main source of production. For both soft and hard tissue regenerations, Nile tilapia skin is being considered as a good source of collagen. Other sources (scales and spine) are less addressed in comparison to skin, which in turn, brings more consistent perspective in relation to clinical use.

Anion-regulated binding selectivity of Cr(III) in collagen.

We present a mechanism for the selectivity of covalent/electrostatic binding of the Cr(III) ion to collagen, mediated by the kosmotropicity of the anions. Although a change in the long-range ordered structure of collagen is observed after covalent binding (Cr(III)-OOC) in the presence of SO4 2- at pH 4.5, the νsym (COO- ) band remains intense, suggesting a relatively lower propensity for the Cr(III) to bind covalently instead of electrostatically through Cr(H2 O)6 3+ . Replacing SO4 2- with Cl- reduces the kosmotropic effect which further favors the electrostatic binding of Cr(III) to collagen. Our findings allow a greater understanding of mechanism-specific metal binding in the collagen molecule. We also report for the first time, surface-enhanced Raman spectroscopy to analyze binding mechanisms in collagen, suggesting a novel way to study chemical modifications in collagen-based biomaterials.

Human dentin characteristics of patients with osteogenesis imperfecta: insights into collagen-based biomaterials

Osteogenesis imperfecta (OI), also known as "brittle bone disease", is a rare genetic disorder of the skeleton, whose most benign form I corresponds to autosomal dominant mutations in the genes encoding type I collagen (COLA1, COLA2). Several associated skeletal manifestations are often observed but, surprisingly, while dentin defects often reflect genetic bone disorders, about half of OI patients have no obvious oral manifestations. Here, we investigated the collagen, mineral and mechanical properties of dentin from deciduous teeth collected from patients with mild form of OI and displaying no obvious clinical signs of dentinogenesis imperfecta. For the first time, an increase in the hardness of OI dentin associated with an increase in mineral content compared to healthy patients was reported. In addition, OI altered the tissue characteristics of the dentin-enamel junction but the interfacial gradient was preserved. The impact of changes in molecular structure due to mutations in OI was assessed by Raman microspectroscopy. Our results highlighted a change in the hydroxyproline-proline ratio in direct association with collagen mineralization. Our findings suggest that the evaluation of teeth could be an important aid for mild types of OI that are often difficult to diagnose clinically and provide experimental evidence that hydroxyproline content should be considered in future studies on collagen-based biomaterials.

Effect of Heat Level and Expose Time on Denaturation of Collagen Tissues.

The applied heat level and expose time are main issues in certain operations/applications, such as a laser assisted tissue welding, preparation of collagen-based biomaterials (films, implants). Therefore, the precise investigation of these parameters is crucial. The results can serve as a guideline to assess potential effects while maintaining the functionality of the collagen structures. Collagen tissues from rat-tail tendon, calfskin, and bones are soaked in buffer solutions, then examined by microscope at different temperature levels. Increase in temperature reduced the microscopically observed collagen crimp contrast for calfskin and rat-tail tendons but not for bone tissues. The contrast level for rat tail tendon decreased down to 80% of its initial value at 37, 157, and 266s for 70, 65, and 60°C, respectively. The decrease in the crimp contrast was about only 25% and 2% at 55 and 50°C after 2h, respectively. 50% drop in contrast level was occurred for the skin samples at 16, 90, 110 and 1900s for 70, 65, and 60°C, respectively. The bone samples, did not show any significant differences in contrast levels. The observed denaturation behaviours are in line with Arrhenius Law. This study could be expanded on to other types of tissues at wider temperature ranges to make a guideline for biological/medical processes that radiate heat in order to assess their side effects on collagen and other proteins.

Collagen-Based Materials Modified by Phenolic Acids-A Review.

Collagen-based biomaterials constitute one of the most widely studied types of materials for biomedical applications. Low thermal and mechanical parameters are the main disadvantages of such structures. Moreover, they present low stability in the case of degradation by collagenase. To improve the properties of collagen-based materials, different types of cross-linkers have been researched. In recent years, phenolic acids have been studied as collagen modifiers. Mainly, tannic acid has been tested for collagen modification as it interacts with a polymeric chain by strong hydrogen bonds. When compared to pure collagen, such complexes show both antimicrobial activity and improved physicochemical properties. Less research reporting on other phenolic acids has been published. This review is a summary of the present knowledge about phenolic acids (e.g., tannic, ferulic, gallic, and caffeic acid) application as collagen cross-linkers. The studies concerning collagen-based materials with phenolic acids are summarized and discussed.

Nucleation and growth of cholesteric collagen tactoids: A time-series statistical analysis based on integration of direct numerical simulation (DNS) and long short-term memory recurrent neural network (LSTM-RNN)

HypothesisLiquid-crystalline phase separation by nucleation and growth (NG) is a crucial step in the formation of collagen-based biomaterials. However, the fundamental mechanisms are not completely understood for chiral lyotropic colloidal mesogens such as collagen. MethodologyTo capture the dynamics of NG under a quenching process into the biphasic equilibrium zone, we use direct numerical simulation based on the time-dependent Ginzburg-Landau model allowing minimization of the total free energy comprised of five key contributions: phase separation (Flory-Huggins), ordering (Landau-de Gennes), chiral orientational elasticity (Frank-Oseen-Mermin), interfacial and coupling effects. LSTM-RNN is applied as a surrogate model to greatly enrich the results. Significant correlations are established using Symbolic Regression. FindingsWe quantify the NG boundaries existing in the collagen phase diagram that has recently been developed and validated by our thermodynamic model (Khadem and Rey, 2019 [1]). We characterize the three NG stages (induction, nucleation, and coarsening) in terms of tactoids’ shape, morphology, growth laws, and population across the NG zone. Wide-range generic correlations are developed, revealing the quench depth dependence of NG characteristics and connecting the sequential NG stages. We confirm experimental observations on time-dependent growth law exponent changes from an initial n≈0.5 for the mass transfer limited regime to n≈1 for the volume-driven phase ordering regime upon increasing quench depth during the nucleation period and having exclusively a value of n≈0.5 for the coarsening period regardless of quench depth. We lastly uncover the underlying physics behind the NG phenomena.

In Vivo Analysis of the Biocompatibility and Immune Response of Jellyfish Collagen Scaffolds and its Suitability for Bone Regeneration.

Jellyfish collagen, which can be defined as “collagen type 0” due to its homogeneity to the mammalian types I, II, III, V, and IX and its batch-to-batch consistent producibility, is of special interest for different medical applications related to (bone) tissue regeneration as an alternative to mammalian collagen-based biomaterials. However, no in vivo studies regarding the induction of M1- and M2-macrophages and their time-dependent ration as well as the analysis of the bone regeneration capacity of jellyfish collagen scaffolds have been conducted until now. Thus, the goal of this study was to determine the nature of the immune response to jellyfish collagen scaffolds and their bone healing capacities. Two in vivo studies using established implantation models, i.e., the subcutaneous and the calvarian implantation model in Wistar rats, were conducted. Furthermore, specialized histological, histopathological, and histomorphometrical methods have been used. As a control biomaterial, a collagen scaffold, originating from porcine pericardium, which has already been stated as biocompatible, was used for the subcutaneous study. The results of the present study show that jellyfish collagen scaffolds are nearly completely resorbed until day 60 post implantation by stepwise integration within the subcutaneous connective tissue mediated mainly by macrophages and single multinucleated giant cells. Interestingly, the degradation process ended in a vessel rich connective tissue that is understood to be an optimal basis for tissue regeneration. The study results showed an overall weaker immune response to jellyfish collagen than to porcine pericardium matrices by the induction of significantly lower numbers of macrophages together with a more balanced occurrence of M1- and M2-macrophages. However, both collagen-based biomaterials induced balanced numbers of both macrophage subtypes, which supports their good biocompatibility. Moreover, the histomorphometrical results for the calvarial implantation of the jellyfish scaffolds revealed an average of 46.20% de novo bone formation at day 60, which was significantly higher compared to the control group. Thereby, the jellyfish collagen scaffolds induced also significantly higher numbers of anti-inflammatory macrophages within the bony implantation beds. Altogether, the results show that the jellyfish collagen scaffolds allowed for a directed integration behavior, which is assumed to be in accordance with the concept of Guided Bone Regeneration (GBR). Furthermore, the jellyfish collagen scaffolds induced a long-term anti-inflammatory macrophage response and an optimal vascularization pattern within their implant beds, thus showing excellent biocompatibility and (bone) tissue healing properties.

Biochemical and structural characterization of sturgeon fish skin collagen (Huso huso).

The potential use of sturgeon fish skin waste (Huso huso), an Iranian major sturgeon species, as a rich source for collagen extraction was evaluated. Yields of ASC and PSC obtained by acidic and enzymatic extractions were 9.98% and 9.08% (based on wet weight), respectively. SDS-PAGE profiles of both collagens led to classification of the proteins as type I with two different α chains (α1 and α2 ). Scanning electron microscopy (SEM) of the collagen sponges indicated dense sheet-like film linked by random-coiled filaments. Glycine was the most predominant amino acid, and the imino acids contents were 21.14% and 21.58% for ASC and PSC, respectively. Fourier-transform infrared spectra (FTIR) confirmed that pepsin digestion did not disrupt PSC triple helical structure. Denaturation and melting temperatures of ASC and PSC were 29.34°C, 92.03°C, and 29.89°C, 88.93°C, respectively. Thus, the sturgeon fish skin waste could serve as an alternative collagenous source for biomedical materials, food, and pharmaceutical applications. PRACTICAL APPLICATIONS: Beluga (Huso huso) is one of the most important sturgeon fish on the Caspian Sea and aquaculture industries. With the exception of the meat and caviar, wastes generated after their processing are usually discarded. Skin and cartilage of sturgeon fish are the by-products of the processing, and they are often discarded as waste or used for low-value purposes, although they are a good source for production of collagen-based biomaterials. Collagen type I is the most abundant collagen in the skin and this work reports the sturgeon fish skin as an important collagen resource with potential for use in the food, biomedical, and cosmetic industries.

Highly biocompatible novel polyphenol cross-linked collagen scaffold for potential tissue engineering applications

Collagen-based biomaterials are known to be the most potential and promising materials with diverse applications in tissue engineering and regeneration, due to its excellent biocompatibility. The major drawback of collagen is its rapid degradation, which can be overcome by crosslinking methods. Polyphenols exhibit excellent antioxidant activity and antimicrobial properties. In the present work, polyphenol-treated collagen scaffold (PPCS) was prepared by treating the aqueous extract of the dried ripe fruits of Terminalia chebula with bovine collagen. Scanning electron microscopy (SEM) of PPCS showed highly oriented interwoven fibrillar collagenous bundles in the network form. The chemical structure modification in PPCS was demonstrated by Fourier Transform Infrared spectroscopy. Tensile property and hydrophilicity of the PPCS showed enhanced values compared to the untreated collagen (COL). The thermal properties of COL and PPC scaffolds investigated by thermogravimetric analysis and differential scanning calorimetry, showed increased thermal decomposition and denaturation temperature values for the polyphenol crosslinked collagen. Further, the PPCS exhibited increased resistance to hydrolysis by collagenase. In vitro studies on biocompatibility showed increased fibroblast cell proliferation on PPCS. Thereby, the physico-chemical and biological properties of PPCS identify it as a promising scaffold with high biocompatibility for applications in tissue engineering and regenerative medicine.

Induction of fiber-like aggregation and gelation of collagen by ultraviolet irradiation at low temperature

Ultraviolet (UV) irradiation is a common method of molecular crosslinking and sterilization of collagen. In this study, UV irradiation at low temperature conditions was investigated as an induction and regulation method for fiber-like aggregation and gelation of collagen. Differences between gelation processes induced by UV irradiation and by traditional temperature-induced methods as well as differences in the properties of the gelation products were systematically analyzed. We found that UV irradiation can induce fiber-like aggregation and gelation of bovine tendon collagen at lower temperatures (<17 °C) than the usual temperature of 37 °C. During UV irradiation, cross-linking and degradation of collagen molecules occurred along with typical collagen fiber formation. The collagen fibers, together with the grafted collagen molecules and the degraded collagen peptides, formed a gel product that had a unique, multi-layered network structure. Collagen gels induced by UV irradiation at low temperatures displayed improved thermal stability, mechanical strength, and cell-growth promoting ability compared with collagen gels that were induced at 37 °C. Our results open up new avenues for the production of collagen-based biomaterials.

Biologization of Collagen-Based Biomaterials Using Liquid-Platelet-Rich Fibrin: New Insights into Clinically Applicable Tissue Engineering.

Platelet-rich fibrin (PRF) is a blood concentrate derived from venous blood that is processed without anticoagulants by a one-step centrifugation process. This three-dimensional scaffold contains inflammatory cells and plasma proteins entrapped in a fibrin matrix. Liquid-PRF was developed based on the previously described low-speed centrifuge concept (LSCC), which allowed the introduction of a liquid-PRF formulation of fibrinogen and thrombin prior to its conversion to fibrin. Liquid-PRF was introduced to meet the clinical demand for combination with biomaterials in a clinically applicable and easy-to-use way. The aim of the present study was to evaluate, ex vivo, the interaction of the liquid-PRF constituents with five different collagen biomaterials by histological analyses. The results first demonstrated that large variability existed between the biomaterials investigated. Liquid-PRF was able to completely invade Mucograft® (MG; Geistlich Biomaterials, Wolhusen, Switzerland) and to partly invade Bio-Gide® (BG; Geistlich Biomaterials, Wolhusen, Switzerland) and Mucoderm® (MD; Botiss Biomaterials, Berlin, Germany), and Collprotect® (CP; Botiss Biomaterials, Berlin, Germany) showed only a superficial interaction. The BEGO® collagen membrane (BCM; BEGO Implant Systems) appeared to be completely free of liquid-PRF. These results were confirmed by the different cellular penetration and liquid-PRF absorption coefficient (PAC) values of the evaluated membranes. The present study demonstrates a system for loading biomaterials with a complex autologous cell system (liquid-PRF) in a relatively short period of time and in a clinically relevant manner. The combination of biomaterials with liquid-PRF may be clinically utilized to enhance the bioactivity of collagen-based biomaterials and may act as a biomaterial-based growth factor delivery system.

Tailoring the collagen film structural properties via direct laser crosslinking of star-shaped polylactide for robust scaffold formation.

Application of restructured collagen-based biomaterials is generally restricted by their poor mechanical properties, which ideally must be close to those of a tissue being repaired. Here, we present an approach to the formation of a robust biomaterial using laser-induced curing of a photosensitive star-shaped polylactide. The created collagen-based structures demonstrated an increase in the Young's modulus by more than an order of magnitude with introduction of reinforcing patterns (from 0.15 ± 0.02 MPa for the untreated collagen to 51.2 ± 5.6 MPa for the reinforced collagen). It was shown that the geometrical configuration of the created reinforcing pattern affected the scaffold's mechanical properties only in the case of a relatively high laser radiation power density, when the effect of accumulated thermomechanical stresses in the photocured regions was significant. Photo-crosslinking of polylactide did not compromise the scaffold's cytotoxicity and provided fluorescent regions in the collagen matrix, that create a potential for noninvasive monitoring of such materials' biodegradation kinetics in vivo.

Oxytetracycline versus Doxycycline Collagen Sponges Designed as Potential Carrier Supports in Biomedical Applications.

Many research studies are directed toward developing safe and efficient collagen-based biomaterials as carriers for drug delivery systems. This article presents a comparative study of the properties of new collagen sponges prepared and characterized by different methods intended for biomedical applications. The structural integrity is one of the main properties for a biomaterial in order for it to be easily removed from the treated area. Thus, the effect of combining a natural polymer such as collagen with an antimicrobial drug such as oxytetracycline or doxycycline and glutaraldehyde as the chemical cross-linking agent influences the cross-linking degree of the material, which is in direct relation to its resistance to collagenase digestion, the drug kinetic release profile, and in vitro biocompatibility. The enzymatic degradation results identified oxytetracycline as the best inhibitor of collagenase when the collagen sponge was cross-linked with 0.5% glutaraldehyde. The drug release kinetics revealed an extended release of the antibiotic for oxytetracycline-loaded collagen sponges compared with doxycycline-loaded collagen sponges. Considering the behavior of differently prepared sponges, the collagen sponge with oxytetracycline and 0.5% glutaraldehyde could represent a viable polymeric support for the prevention/treatment of infections at the application site, favoring tissue regeneration.

Theoretical Platform for Liquid-Crystalline Self-Assembly of Collagen-Based Biomaterials

The collagen triple helix is a ubiquitous biomacromolecule used in acidic aqueous solutions as precursor in the fabrication of artificial compact bone and cornea and in tissue engineering. The primary architecture of these highly structured solid tissues is formed during the cholesteric liquid-crystalline stage of their morphogenesis. The theoretical platform that describes the coupled dynamics of phase-ordering and mass transfer developed, implemented and validated here can be used for optimal material design and plays a significant complementary role to future experimental studies. Based on uniaxiality assumption, we have recently developed and validated a theory for the free energy tailored for acidic collagenous dispersions. Here we significantly expand and generalize our previous study, by including biaxiality since cholesteric phases must have a degree of biaxiality. In this work, we first modify the proposed interchain interaction and excluded-volume contribution by use of the addition theorem for spherical harmonics. Then, the Euler-Lagrange minimization followed by expansion around I/N* transition allows us to construct the free energy of ordering in terms of the phenomenological Landau–de Gennes formulation. Finally, we use the time-dependent Ginzburg-Landau equations to study the non-Fickian evolution of a single two dimensional cholesteric tactoid through a shallow quench from the isotropic to biphasic region of the phase diagram. Although equilibrium biaxiality is considerably low for these long-pitch cholesterics, we found that during self-assembly the biaxial order parameter achieves significant larger values than the equilibrium value. Additionally, the relaxed director field becomes both onion-like and defect-less, which is consistent with the twisted bipolar structure observed experimentally. The self-assembly simulations demonstrate that the formulated theoretical platform is not only consistent with previous theoretical and experimental studies but also able to be used to explore new routes for non-equilibrium collagen self-assembly. Taken together, this study deepens our understanding of cholesteric (chiral nematic N*) mesophase in acidic solutions of tropocollagen, and suggests a systematic spatio-temporal model that is capable of being used to extract the engineering principles for processing of these sought-after biomaterials.

Acoustic modification of collagen hydrogels facilitates cellular remodeling.

Developing tunable biomaterials that have the capacity to recreate the physical and biochemical characteristics of native extracellular matrices (ECMs) with spatial fidelity is important for a variety of biomedical, biological, and clinical applications. Several factors have made the ECM protein, collagen I, an attractive biomaterial, including its ease of isolation, low antigenicity and toxicity, and biodegradability. However, current collagen gel formulations fail to recapitulate the range of collagen structures observed in native tissues, presenting a significant challenge in achieving the full potential of collagen-based biomaterials. Collagen fiber structure can be manipulated in vitro through mechanical forces, environmental factors, or thermal mechanisms. Here, we describe a new ultrasound-based fabrication technology that exploits the ability of ultrasound to generate localized mechanical forces to control the collagen fiber microstructure non-invasively. The results indicate that exposing soluble collagen to ultrasound (7.8 or 8.8 ​MHz; 3.2–10 ​W/cm2) during hydrogel formation leads to local variations in collagen fiber structure and organization that support increased levels of cell migration. Furthermore, multiphoton imaging revealed increased cell-mediated collagen remodeling of ultrasound-exposed but not sham-exposed hydrogels, including formation of multicellular aggregates, collagen fiber bundle contraction, and increased binding of collagen hybridizing peptides. Skin explant ​cultures obtained from diabetic mice showed similar enhancement of cell-mediated remodeling of ultrasound-exposed but not sham-exposed collagen hydrogels. Using the mechanical forces associated with ultrasound to induce local changes in collagen fibril structure and organization ​to functionalize native biomaterials is a promising non-invasive and non-toxic technology for tissue engineering and regenerative medicine.