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Introduction: Excessive bleeding in trauma and surgical settings leads to increased operative time, reoperation rates, and overall healthcare costs. A wide range of hemostatic agents have been developed to control bleeding that can vary considerably in type of hemostatic action, ease of application, cost, risk of infection, and dependence on patient coagulation. Microfibrillar collagen-based hemostatic materials (MCH) have yielded beneficial results in a variety of applications., Methods: A new flowable collagen product, containing a modified MCH flour, but in a more convenient flowable delivery system, was evaluated for hemostatic efficacy in preclinical models of solid organ injury and spinal cord exposure. The primary objective of this study was to compare the hemostatic potential and local tissue responses to this novel, flowable collagen-based hemostatic agent to the original flour formulation to confirm that the new method of delivery did not interfere with the hemostatic properties of the MCH flour., Results: When observed visually, the flowable MCH flour mixed with saline (FL) provided more precise application and uniform coverage to injured tissues compared to the dry MCH flour alone (F 0 ). All of the treatments (FL, F 0 , and gauze) exhibited comparable Lewis bleed grade at all three time points evaluated in the capsular resection liver injury model (bleed grade: 1.0-1.3; p > 0.05 in all cases). FL and F 0 exhibited comparable 100% acute hemostatic efficacy and similar long-term histomorphological properties (up to 120 days) in a capsular resection liver injury in pigs, while gauze resulted in significantly lower rates of acute hemostatic efficacy (8-42%, p <0.05 in all cases). In an ovine model of dorsal laminectomy and durotomy, FL and F 0 again exhibited comparable results without any neurological effects., Conclusion: Flowable microfibrillar collagen was shown to yield favorable short- and long-term outcomes in two representative applications where hemostatic efficacy is critical to surgical success., Competing Interests: Dr. Bradbury, Mrs. Gagne and Dr. Badhwar are employees of BD. Dr. Lake is a consultant for and Dr. Deeken is the owner of Covalent Bio, LLC, which received funding from BD for this project. Dr. Bohnen is a consultant for BD. Dr. Deeken reports consulting fees from BD for manuscript preparation, during the conduct of the study; she also reports consulting fees for unrelated projects from BD, Medtronic, SurgiMatrix, Tissium, Surgical Innovation Associates, Osteogenics, Polynovo, MedSkin Solutions, Aran Biomedical, Ethicon (Johnson & Johnson), Americas Hernia Society Quality Collaborative, Colorado Therapeutics, and TELABio, outside the submitted work; In addition, Dr. Deeken has patents in bionanocomposite materials broadly related to the field of hernia repair (patent numbers: 2009293001, 2334257 2,334,257UK 602009046407.8, 2,334,257FR, 16/043,849, 2,737,542) issued to University of Missouri. The authors report no other conflicts of interest in this work., (© 2023 Lake et al.)

Diabetes mellitus (DM) is associated with musculoskeletal complications-including tendon dysfunction and injury. Patients with DM show altered foot and ankle mechanics that have been attributed to tendon dysfunction as well as impaired recovery post-tendon injury. Despite the problem of DM-related tendon complications, treatment guidelines specific to this population of individuals are lacking. DM impairs tendon structure, function, and healing capacity in tendons throughout the body, but the Achilles tendon is of particular concern and most studied in the diabetic foot. At macroscopic levels, asymptomatic, diabetic Achilles tendons may show morphological abnormalities such as thickening, collagen disorganization, and/or calcific changes at the tendon enthesis. At smaller length scales, DM affects collagen sliding and discrete plasticity due to glycation of collagen. However, how these alterations translate to mechanical deficits observed at larger length scales is an area of continued investigation. In addition to dysfunction of the extracellular matrix, tendon cells such as tenocytes and tendon stem/progenitor cells show significant abnormalities in proliferation, apoptosis, and remodeling capacity in the presence of hyperglycemia and advanced glycation end-products, thus contributing to the disruption of tendon homeostasis and healing. Improving our understanding of the effects of DM on tendons-from molecular pathways to patients-will progress toward targeted therapies in this group at high risk of foot and ankle morbidity.

Background: Post-traumatic joint contracture (PTJC), characterized by loss of motion and permanent stiffness, affects up to 50% of patients following elbow joint dislocation or fracture. Mechanisms governing successful conservative treatment methods aimed at preventing elbow PTJC and avoiding operative treatments (e.g., physical therapy) are poorly understood. Using a previously established rat model of elbow PTJC, the purpose of this study was to explore the effect of varying timing, intensity and duration of active, functional exercise on joint motion outcomes., Methods: Following a surgically-induced unilateral elbow dislocation in rats, injured limbs were immobilized in bandages for 42 days followed by free mobilization for 42 additional days producing long-term PTJC. This work summarizes several studies (Phases I-III) that investigated the effects of early versus delayed therapy (timing), free mobilization versus forced treadmill walking (intensity), and limited-time versus unlimited use (duration) on elbow PTJC., Results: Joint motion outcomes in therapy groups showed no improvements compared to non-treated injured animals when therapy began day 14 post-injury or later regardless of timing, intensity or duration. Improved joint range-of-motion was only achieved when bandages were permanently removed at day 3 post-injury, regardless of whether added treadmill walking was performed., Conclusion: Early motion is essential to preserving range-of-motion following traumatic elbow injury in a rat model., Competing Interests: CONFLICT OF INTEREST The authors declare that they have no conflict of interests (28).

Background: The elbow is highly susceptible to contracture, which affects up to 50% of patients who experience elbow trauma. Previously, we developed a rat model to study elbow contracture that exhibited features similar to the human condition, including persistently decreased ROM and increased capsule thickness/adhesions. However, elbow ROM was not quantitatively evaluated over time throughout contracture development and subsequent mobilization of the joint., Questions/purposes: The purposes of this study were (1) to quantify the time-dependent mechanics of contracture, including comparison of contracture after immobilization and free mobilization; and (2) to determine what changes occur in capsule and joint surface morphology that may support the altered joint mechanics., Methods: A total of 96 male Long-Evans rats were randomized into control and injury (unilateral soft tissue injury/immobilization) groups. Flexion-extension and pronation-supination joint mechanics (n = 8/group) were evaluated after 3, 7, 21, or 42 days of immobilization (IM) or after 42 days of IM with either 21 or 42 days of free mobilization (63 or 84 FM, respectively). After measuring joint mechanics, a subset of these limbs (n = 3/group) was prepared for histologic analysis and blinded sections were scored to evaluate capsule and joint surface morphology. Joint mechanics and capsule histology at 42 IM and 84 FM were reported previously but are included to demonstrate the full timeline of elbow contracture., Results: In flexion-extension, injured limb ROM was decreased compared with control (103° ± 11°) by 21 IM (70° ± 13°) (p = 0.001). Despite an increase in injured limb ROM from 42 IM (55° ± 14°) to 63 FM (83° ± 10°) (p < 0.001), injured limb ROM was still decreased compared with control (103° ± 11°) (p = 0.002). Interestingly, ROM recovery plateaued because there was no difference between injured limbs at 63 (83° ± 10°) and 84 FM (73° ± 19°) (p > 0.999). In pronation-supination, increased injured limb ROM occurred until 7 IM (202° ± 32°) compared with control (155° ± 22°) (p = 0.001), representative of joint instability. However, injured limb ROM decreased from 21 (182° ± 25°) to 42 IM (123° ± 47°) (p = 0.001), but was not different compared with control (155° ± 22°) (p = 0.108). Histologic evaluation showed morphologic changes in the anterior capsule (increased adhesions, myofibroblasts, thickness) and nonopposing joint surfaces (surface irregularities with tissue overgrowth, reduced matrix), but these changes did not increase with time., Conclusions: Overall, flexion-extension and pronation-supination exhibited distinct time-dependent patterns during contracture development and joint mobilization. Histologic evaluation showed tissue changes, but did not fully explain the patterns in contracture mechanics. Future work will use this rat model to evaluate the periarticular soft tissues of the elbow to isolate tissue-specific contributions to contracture to ultimately develop strategies for tissue-targeted treatments., Clinical Relevance: A rat model of posttraumatic elbow contracture quantitatively described contracture development/progression and reiterates the need for rehabilitation strategies that consider both flexion-extension and pronation-supination elbow motion.

Locomotive changes are often associated with disease or injury, and these changes can be quantified through gait analysis. Gait analysis has been applied to preclinical studies, providing quantitative behavioural assessment with a reasonable clinical analogue. However, available gait analysis technology for small animals is somewhat limited. Furthermore, technological and analytical challenges can limit the effectiveness of preclinical gait analysis. The Gait Analysis Instrumentation and Technology Optimized for Rodents (GAITOR) Suite is designed to increase the accessibility of preclinical gait analysis to researchers, facilitating hardware and software customization for broad applications. Here, the GAITOR Suite's utility is demonstrated in 4 models: a monoiodoacetate (MIA) injection model of joint pain, a sciatic nerve injury model, an elbow joint contracture model, and a spinal cord injury model. The GAITOR Suite identified unique compensatory gait patterns in each model, demonstrating the software's utility for detecting gait changes in rodent models of highly disparate injuries and diseases. Robust gait analysis may improve preclinical model selection, disease sequelae assessment, and evaluation of potential therapeutics. Our group has provided the GAITOR Suite as an open resource to the research community at www.GAITOR.org , aiming to promote and improve the implementation of gait analysis in preclinical rodent models.

There is a substantial prevalence of post-operative incisional hernia for both laparoscopic and laparotomy procedures, but there have been few attempts at quantifying abdominal wound closure methodology in the literature. One method to ascertain a more robust method of wound closure is the identification of the influence of suture placement parameters on suture pullout force. Current surgical practice involves a recommended bite depth and bite separation of 10mm, but the evidence base for this is not clear. In this paper, the suture pullout characteristics of both porcine and human linea alba were investigated to ascertain a suture placement protocol for surgical wound closure. Uniaxial suture pullout force testing on fresh frozen porcine and human linea alba samples was performed using standard materials testing machines. The influence of the number of suture loops, the bite depth and the bite separation of the sutures and the orientation of the sutures with respect to the principal fibre direction in the linea alba were assessed. Results showed a clearly identifiable relationship between pullout force of the suture, bite separation and bite depth, with low suture separation and high suture depth as optimal parameters for increasing pullout force. Resistance to pullout could be improved by as much as 290% when optimizing test conditions. Both human and porcine tissue were observed to exhibit very similar pullout force characteristics, corroborating the use of a porcine model for investigations into wound closure methodology. Orientation of suture application was also found to significantly affect the magnitude of suture pullout, with suturing applied longitudinally across a transverse defect resulting in higher pullout forces for small suture bite separations. Although further assessment in an environment more representative of in vivo conditions is required, these findings indicate that increasing the bite depth and reducing the bite separation with respect to the current surgical recommendations may reduce the risk of post-operative incisional hernia., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Post-traumatic joint contracture (PTJC) in the elbow is a challenging clinical problem due to the anatomical and biomechanical complexity of the elbow joint., Methods: We previously established an animal model to study elbow PTJC, wherein surgically induced soft tissue damage, followed by 6 weeks of unilateral immobilization in Long-Evans rats, led to stiffened and contracted joints that exhibited features similar to the human condition. In this study, after 6 weeks of immobilization, we remobilized the animal (ie, external bandage removed and free cage activity) for an additional 6 weeks, after which the limbs were evaluated mechanically and histologically. The objective of this study was to evaluate whether this decreased joint motion would persist after 6 weeks of free mobilization (FM)., Results: After FM, flexion-extension demonstrated decreased total range of motion (ROM) and neutral zone length, and increased ROM midpoint for injured limbs compared with control and contralateral limbs. Specifically, after FM total ROM demonstrated a significant decrease of approximately 22% and 26% compared with control and contralateral limbs for injury I (anterior capsulotomy) and injury II (anterior capsulotomy with lateral collateral ligament transection), respectively. Histologic evaluation showed increased adhesion, fibrosis, and thickness of the capsule tissue in the injured limbs after FM compared with control and contralateral limbs, which is consistent with patterns previously reported in human tissue., Conclusion: Even with FM, injured limbs in this model demonstrate persistent joint motion loss and histologic results similar to the human condition. Future work will use this animal model to investigate the mechanisms responsible for PTJC and responses to therapeutic intervention., (Copyright © 2017 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.)

Human supraspinatus tendon (SST) exhibits region-specific nonlinear mechanical properties under tension, which have been attributed to its complex multiaxial physiological loading environment. However, the mechanical response and underlying multiscale mechanism regulating SST behavior under other loading scenarios are poorly understood. Furthermore, little is known about the contribution of elastin to tendon mechanics. We hypothesized that (1) SST exhibits region-specific shear mechanical properties, (2) fiber sliding is the predominant mode of local matrix deformation in SST in shear, and (3) elastin helps maintain SST mechanical integrity by facilitating force transfer among collagen fibers. Through the use of biomechanical testing and multiphoton microscopy, we measured the multiscale mechanical behavior of human SST in shear before and after elastase treatment. Three distinct SST regions showed similar stresses and microscale deformation. Collagen fiber reorganization and sliding were physical mechanisms observed as the SST response to shear loading. Measures of microscale deformation were highly variable, likely due to a high degree of extracellular matrix heterogeneity. After elastase treatment, tendon exhibited significantly decreased stresses under shear loading, particularly at low strains. These results show that elastin contributes to tendon mechanics in shear, further complementing our understanding of multiscale tendon structure-function relationships., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Although linked to several vitreoretinal pathologies including traumatic retinal tears, breaks, and symptomatic vitreomacular traction, the dynamic material behavior of the vitreous body in response to mechanical loads is not well understood. The purpose of this study was to evaluate spatiotemporal patterns of collagen fiber reorganization and vitreous deformation (strain) in response to tensile and compressive forces. Using thick slabs of bovine eyes we examined collagen fiber reorganization following tensile and compressive step-loading with quantitative polarized light imaging. Strains were measured from sparse marker arrays and temporal collagen behavior was estimated from creep compliance rheological tests. Results showed that under applied loads (1) collagen fibers became significantly more aligned at the vitreous base (near the pars plana and the ciliary body), (2) vitreous located directly behind the lens deformed significantly more than surrounding regions, and (3) changes in collagen fiber alignment occurred on a short (<5 s) timescale. Together these results show that, despite a homogeneous visual appearance, the vitreous body exhibits anisotropic material behavior in tension and compression. Spatiotemporal patterns of collagen rearrangement were consistent with epidemiological patterns of traumatic retinal damage and vitreoretinal topology. High strains in the vitreous corresponded with locations of lower collagen content that are prone to age-related degeneration. These data suggest that differential fiber alignment and mechanical deformation could contribute to the pathogenesis of these diseases. Computational models that incorporate these experimental data will help improve our understanding of the biomechanical mechanisms that contribute to the pathogenesis of traumatic retinal damage, vitreous degeneration, and vitreoretinal disease.

Tissue-equivalents (TEs), simple model tissues with tunable properties, have been used to explore many features of biological soft tissues. Absent in most formulations however, is the residual stress that arises due to interactions among components with different unloaded levels of stress, which has an important functional role in many biological tissues. To create a pre-stressed model system, co-gels were fabricated from a combination of hyaluronic acid (HA) and reconstituted Type-I collagen (Col). When placed in solutions of varying osmolarity, HA-Col co-gels swell as the HA imbibes water, which in turn stretches (and stresses) the collagen network. In this way, co-gels with residual stress (i.e., collagen fibers in tension and HA in compression) were fabricated. When the three gel types tested here were immersed in hypotonic solutions, pure HA gels swelled the most, followed by HA-Col co-gels; no swelling was observed in pure collagen gels. The greatest swelling rates and swelling ratios occurred in the lowest salt concentration solutions. Tension on the collagen component of HA-Col co-gels was calculated from a stress balance and increased nonlinearly as swelling increased. The swelling experiment results were in good agreement with the stress predicted by a fibril network + non-fibrillar interstitial matrix computational model., Competing Interests: There are no conflicts of interest.

Previous studies have shown different elastic properties between the anteromedial (AM) and posterolateral (PL) bundles of the human anterior cruciate ligament (ACL). However, it is unknown if the two bundles of the ACL exhibit distinct time-dependent properties and microstructural organization, which have important implications for fully understanding the structure-function relationships of this oft-injured ligament. The goal of this study was to quantify the viscoelastic material properties and collagen fiber alignment of the AM and PL bundles in 16 human ACLs during stress-relaxation mechanical tests using the quasi-linear viscoelastic (QLV) model and a quantitative polarization imaging technique. We hypothesized that the AM and PL bundles would exhibit differences in the instantaneous mechanical and organizational properties (i.e., immediately following a step increase in strain), but similar time-dependent changes during stress-relaxation. Results showed that AM samples exhibited larger peak/equilibrium stresses and less stress-relaxation during a 300-s hold compared to PL samples. The AM bundle demonstrated stronger and more uniform collagen fiber alignment (i.e., higher degree of linear polarization (DoLP) values and less distributed angle of polarization (AoP) values) compared to the PL bundle, and larger changes in alignment strength during the hold. Results suggest that the AM bundle is the more "dominant" bundle, with significantly different mechanical and material properties in stress-relaxation. While more research is needed to better understand how these findings relate to the pathophysiology of ACL tears and can best guide treatment, the findings provide additional insight into the microstructural properties and biomechanics of the human ACL., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Over 100 types of soft tissue repair materials are commercially available for hernia repair applications. These materials vary in characteristics such as mesh density, pore size, and pore shape. It is difficult to determine the impact of a single variable of interest due to other compounding variables in a particular design. Thus, the current study utilized prototype meshes designed to evaluate each of these mesh parameters individually., Methods: Five prototype meshes composed of planar, monofilament polyethylene terephthalate (PET) were evaluated in this study. The meshes were designed to focus on three key parameters, namely mesh density, pore size, and pore shape. The prototype meshes were implanted in the preperitoneal, retrorectus space in a porcine model of ventral incisional hernia repair, and tissue ingrowth characteristics were evaluated after 90 days. Mesh-tissue composite specimens were obtained from each repair site and evaluated via T-peel mechanical testing. Force-displacement data for each T-peel test were analyzed and five characteristics of tissue ingrowth reported: peak force (fp), critical force (fc), fracture energy (Γc), work (W), and work density (Wden). Hematoxylin and eosin (H&E) stained sections of explanted mesh-tissue composites were also assessed for characteristics of tissue response including cellular infiltration, cell types, inflammatory response, extracellular matrix deposition, neovascularization, and fibrosis, with a composite score assigned to represent overall tissue response., Results: The medium-weight, very large pore, hexagonal (MWVLH) mesh performed significantly better than the light-weight, medium pore, diamond (LWMD) mesh for all parameters evaluated (fp, fc, Γc, W, Wden) and trended toward better results than the medium-weight, medium pore, diamond (MWMD) mesh for the majority of the parameters evaluated. When the data for the five meshes was grouped to evaluate mesh density, pore size, and pore shape, differences were more pronounced. No significant differences were observed with respect to mesh density, however significant improvement in mechanical strength of tissue ingrowth occurred as pore size increased from medium to very large. In addition, the hexagonal pores resulted in the strongest tissue ingrowth, followed by the square pores, and finally the diamond pores. Scores for several histological parameters were significantly different for these prototype meshes. For example, the MWVLH mesh showed significantly greater tissue ingrowth by neovascularization histological score than MWMD and MWVLS meshes (p<0.05) and significantly less fibrosis than LWMD and MWVLS meshes (p<0.05)., Conclusion: Pore shape and pore size significantly altered the mechanical strength of tissue ingrowth and host-site integration in a porcine model of ventral hernia repair, while mesh density had no effect., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Purpose: Collagen fiber remodeling in the vitreous body has been implicated in cases of vitreomacular traction, macular hole, and retinal detachment, and also may occur during pharmacologic vitreolysis. The purpose of this study was to evaluate quantitative polarized light imaging (QPLI) as a tool for studying fiber organization in the vitreous and near the vitreoretinal interface in control and enzymatically perturbed conditions., Methods: Fiber alignment was measured in anterior-posterior sections of bovine and porcine vitreous. Additional tests were performed on bovine lenses and nasal-temporal vitreous sections. Effects of proteoglycan degradation on collagen fiber alignment using trypsin and plasmin were assessed at the microstructural level using electron microscopy and at the global level using QPLI., Results: Control vitreous showed fiber organization patterns consistent with the literature across multiple-length scales, including the global anterior-posterior coursing of vitreous fibers, as well as local fibers parallel to the equatorial vitreoretinal interface and transverse to the posterior interface. Proteoglycan digestion with trypsin or plasmin significantly increased fiber alignment throughout the vitreous (P < 0.01). The largest changes (3×) occurred in the posterior vitreous where fibers are aligned transverse to the posterior vitreoretinal interface (P < 0.01)., Conclusions: Proteoglycan loss due to enzymatic vitreolysis differentially increases fiber alignment at locations where tractions are most common. We hypothesize that a similar mechanism leads to retinal complications during age-related vitreous degeneration. Structural changes to the entire vitreous body (as opposed to the vitreoretinal interface alone) should be evaluated during preclinical testing of pharmacological vitreolysis candidates., (Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.)

Background: Over the past 60 years, the soft tissue repair market has grown to include over 50 types of hernia repair materials. Surgeons typically implant these materials in the orientation that provides maximum overlap of the mesh over the defect, with little regard for mechanical properties of the mesh material. If the characteristics of the meshes were better understood, an appropriate material could be identified for each patient, and meshes could be placed to optimize integration with neighboring tissue and avoid the mechanical mis-match that can lead to impaired graft fixation. The purpose of this study was to fully characterize and compare the mechanical properties of thirteen types of hernia repair materials via planar biaxial tensile testing., Methods: Equibiaxial (i.e., equal simultaneous loading in both directions) and strip biaxial (i.e., loading in one direction with the other direction held fixed) tests were utilized as physiologically relevant loading regimes. After applying a 0.1N pre-load on each arm, samples were subjected to equibiaxial cyclic loading using a triangular waveform to 2.5mm displacement on each arm at 0.1Hz for 10 cycles. Samples were then subjected to two strip biaxial tests (using the same cyclic loading protocol), where extension was applied along a single axis with the other axis held fixed., Results: The thirteen evaluated mesh types exhibited a wide range of mechanical properties. Some were nearly isotropic (C-QUR™, DUALMESH(®), PHYSIOMESH™, and PROCEED(®)), while others were highly anisotropic (Ventralight™ ST, Bard™ Mesh, and Bard™ Soft Mesh). Some displayed nearly linear behavior (Bard™ Mesh), while others were non-linear with a long toe region followed by a sharp rise in tension (INFINIT(®)). These materials are currently utilized in clinical settings as if they are uniform and interchangeable, and clearly this is not the case. The mechanical properties most advantageous for successful hernia repairs are currently only vaguely described in the clinical literature. The characteristics of the human abdominal wall must be extensively characterized to provide a thorough understanding of the tissue being reinforced/replaced by these meshes. A better understanding of these mechanical differences would enable matching of patient characteristics to a specific mesh with the properties best suited to that particular repair., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Tendons in different locations function in unique, and at times complex, in vivo loading environments. Specifically, some tendons are subjected to compression, shear and/or torsion in addition to tensile loading, which play an important role in regulating tendon properties. To date, there have been few studies evaluating tendon mechanics when loaded in compression and shear, which are particularly relevant for understanding tendon regions that experience such non-tensile loading during normal physiologic function. The objective of this study was to evaluate mechanical responses of different regions of bovine deep digital flexor tendons (DDFT) under compressive and shear loading, and correlate structural characteristics to functional mechanical properties. Distal and proximal regions of DDFT were evaluated in a custom-made loading system via three-step incremental stress-relaxation tests. A two-relaxation-time solid linear model was used to describe the viscoelastic response. Results showed large differences in the elastic behavior between regions: distal region stresses were 4-5 times larger than proximal region stresses during compression and 2-3 times larger during shear. Surprisingly, the viscous (i.e., relaxation) behavior was not different between regions for either compression or shear. Histological analysis showed that collagen and proteoglycan in the distal region distributed differently from the proximal region. Results demonstrate mechanical differences between two regions of DDFT under compression and shear loading, which are attributed to variations of composition and microstructural organization. These findings deepen our understanding of structure-function relationships of tendon, particularly for tissues adapted to supporting combinations of tension, compression, and shear in physiological loading environments., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Collagen and fibrin are important extracellular matrix (ECM) components in the body, providing structural integrity to various tissues. These biopolymers are also common scaffolds used in tissue engineering. This study investigated how co-gelation of collagen and fibrin affected the properties of each individual protein network. Collagen-fibrin co-gels were cast and subsequently digested using either plasmin or collagenase; the microstructure and mechanical behavior of the resulting networks were then compared with the respective pure collagen or fibrin gels of the same protein concentration. The morphologies of the collagen networks were further analyzed via three-dimensional network reconstruction from confocal image z-stacks. Both collagen and fibrin exhibited a decrease in mean fiber diameter when formed in co-gels compared with the pure gels. This microstructural change was accompanied by an increased failure strain and decreased tangent modulus for both collagen and fibrin following selective digestion of the co-gels. In addition, analysis of the reconstructed collagen networks indicated the presence of very long fibers and the clustering of fibrils, resulting in very high connectivities for collagen networks formed in co-gels., (Copyright © 2012 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

While several studies have evaluated how the degree of collagen alignment affects the response of soft tissues to tensile loading, the role of fibrillar organization in indentation is less understood. Collagen-based tissue-equivalents (TEs) provide a convenient model system to explore structure-function relationships since their microstructural properties can be easily controlled during fabrication. The purpose of this study was to evaluate the role of initial collagen alignment on the mechanical and structural behavior of soft tissues subjected to indentation using TEs as a model system. Cell-compacted TEs with either isotropic or highly anisotropic fiber alignment were subjected to four-step incremental stress-relaxation indentation tests. The mechanical properties, collagen reorganization and 2D strain patterns were quantified at each indentation step and compared between groups. While no differences were seen in the peak force response, significant differences were seen in relaxation behavior, fiber kinematics and tissue strain. Specifically, highly aligned samples exhibited a slower relaxation rate, smaller changes in collagen fiber orientation, larger changes in strength of alignment, and larger strain magnitudes compared to isotropic samples. Results demonstrate the significant role that microstructural organization plays in mediating the response of soft tissues to a non-tensile (i.e., indentation) mechanical stimulus., (Copyright © 2012 Elsevier Ltd. All rights reserved.)