Removal of the infrapatellar fat pad and associated synovium benefits female guinea pigs in the Dunkin Hartley model of idiopathic osteoarthritis.

Background: Several tissues contribute to the onset and advancement of knee osteoarthritis (OA). One tissue type that is worthy of closer evaluation, particularly in the context of sex, is the infrapatellar fat pad (IFP). We previously demonstrated that removal of the IFP had short-term beneficial effects for a cohort of male Dunkin-Hartley guinea pigs. The present project was designed to elucidate the influence of IFP removal in females of this OA-prone strain. It was hypothesized that resection of the IFP would reduce the development of OA in knees of a rodent model predisposed to the disease. Methods: Female guinea pigs (n=16) were acquired at an age of 2.5 months. Surgical removal of the IFP and associated synovium complex (IFP/SC) was executed at 3 months of age. One knee had the IFP/SC resected; a comparable sham surgery was performed on the contralateral knee. All animals were subjected to voluntary enclosure monitoring and dynamic weight-bearing, as well as compulsory treadmill-based gait analysis monthly; baseline data was collected prior to surgery. Guinea pigs were euthanized at 7 months. Knees from eight animals were evaluated via histology, mRNA expression, and immunohistochemistry (IHC); knees from the remaining eight animals were allocated to microcomputed tomography (microCT), biomechanical analyses (whole joint testing and indentation relaxation testing), and atomic absorption spectroscopy (AAS). Results: Fibrous connective tissue (FCT) replaced the IFP/SC. Mobility/gait data indicated that unilateral IFP/SC removal did not affect bilateral hindlimb movement. MicroCT demonstrated that osteophytes were not a significant feature of OA in this sex; however, trabecular thickness (TbTh) in medial femorae decreased in knees containing the FCT. Histopathology scores were predominantly influenced by changes in the lateral tibia, which demonstrated that histologic signs of OA were increased in knees containing the native IFP/SC versus those with the FCT. Similarly, indentation testing demonstrated higher instantaneous and equilibrium moduli in the lateral tibial articular cartilage of control knees with native IFPs. AAS of multiple tissue types associated with the knee revealed that zinc was the major trace element influenced by removal of the IFP/SC. Conclusions: Our data suggest that the IFP/SC is a significant component driving knee OA in female guinea pigs and that resection of this tissue prior to disease has short-term benefits. Specifically, the formation of the FCT in place of the native tissue resulted in decreased cartilage-related OA changes, as demonstrated by reduced Osteoarthritis Research Society International (OARSI) histology scores, as well as changes in transcript, protein, and cartilage indentation analyses. Importantly, this model provides evidence that sex needs to be considered when investigating responses and associated mechanisms seen with this intervention.

Early removal of the infrapatellar fat pad/synovium complex beneficially alters the pathogenesis of moderate stage idiopathic knee osteoarthritis in male Dunkin Hartley guinea pigs.

BACKGROUND: The infrapatellar fat pad (IFP) is the largest adipose deposit in the knee; however, its contributions to the homeostasis of this organ remain undefined. To determine the influence of the IFP and its associated synovium (IFP/synovium complex or IFP/SC) on joint health, this study evaluated the progression of osteoarthritis (OA) following excision of this unit in a rodent model of naturally-occurring disease. METHODS: Male Dunkin-Hartley guinea pigs (n=18) received surgical removal of the IFP in one knee at 3 months of age; contralateral knees received sham surgery as matched internal controls. Mobility and gait assessments were performed prior to IFP/SC removal and monthly thereafter. Animals were harvested at 7 months of age. Ten set of these knees were processed for microcomputed tomography (microCT), histopathology, transcript expression analyses, and immunohistochemistry (IHC); 8 sets of knees were dedicated to microCT and biomechanical testing (material properties of knee joints tissues and anterior drawer laxity). RESULTS: Fibrous connective tissue (FCT) developed in place of the native adipose depot. Gait demonstrated no significant differences between IFP/SC removal and contralateral hindlimbs. MicroCT OA scores were improved in knees containing the FCT. Quantitatively, IFP/SC-containing knees had more osteophyte development and increased trabecular volume bone mineral density (vBMD) in femora and tibiae. Histopathology confirmed maintenance of articular cartilage structure, proteoglycan content, and chondrocyte cellularity in FCT-containing knees. Transcript analyses revealed decreased expression of adipose-related molecules and select inflammatory mediators in FCTs compared to IFP/SCs. This was verified via IHC for two key inflammatory agents. The medial articular cartilage in knees with native IFP/SCs showed an increase in equilibrium modulus, which correlated with increased amounts of magnesium and phosphorus. DISCUSSION/CONCLUSION: Formation of the FCT resulted in reduced OA-associated changes in both bone and cartilage. This benefit may be associated with: a decrease in inflammatory mediators at transcript and protein levels; and/or improved biomechanical properties. Thus, the IFP/SC may play a role in the pathogenesis of knee OA in this strain, with removal prior to disease onset appearing to have short-term benefits.

Osteoarthritic meniscal entheses exhibit altered collagen fiber orientation.

PURPOSE/AIM: The knee menisci are vital for maintaining the stability of the joint, allowing for force distribution, and protecting the underlying articular cartilage during loading. Each meniscus is attached to the underlying bone via two ligamentous entheses composed of collagen fibers that are continuous throughout all four zones of the attachment: ligament, uncalcified fibrocartilage, calcified fibrocartilage, and subchondral bone. The collagen fibers of the meniscal entheses are important for proper functionality of the entheses, particularly in preventing meniscal extrusion which is a common hallmark of osteoarthritis. The goal of this work was to assess changes in collagen fiber orientation present in osteoarthritic knee joints. MATERIALS AND METHODS: Entheses were harvested from patients undergoing total knee arthroplasties and prepared histological sections were stained with picrosirius red to identify collagen fiber angle and fiber deviation. RESULTS: In the calcified fibrocartilage the collagen fibers of the lateral anterior enthesis inserted at significantly (p < 0.1) shallower angles, and the fiber deviation was significantly (p < 0.1) less compared to the lateral posterior enthesis. These differences in the calcified fibrocartilage may occur as an adaptation to loading regimes of the osteoarthritic joint. When compared to the collagen fiber orientation of healthy entheses, collagen fibers in osteoarthritic tissue inserted at shallower insertion angles and demonstrated higher levels of deviation. CONCLUSIONS: Changes to meniscal enthesis collagen fiber orientation with end stage osteoarthritis could offer an explanation for the change in functionality of diseased tissue and may contribute to meniscal extrusion and ultimately the degeneration of articular cartilage.

Evaluating the Efficacy of Combined P188 Treatment and Surgical Intervention in Preventing Post-Traumatic Osteoarthritis Following a Traumatic Knee Injury.

Previous studies have shown that reconstructive surgery alone following injury to the anterior cruciate ligament (ACL) does not prevent the development of post-traumatic osteoarthritis (PTOA). Poloxamer 188 (P188) has been shown to prevent cell death following trauma in both articular cartilage and meniscal tissue. This study aims to test the efficacy of single or multiple administrations of P188 in conjunction with reconstructive surgery to help prevent or delay the onset of the disease. Thirty skeletally mature rabbits underwent closed-joint trauma that resulted in ACL rupture and meniscal damage and were randomly assigned to one of four treatment groups with varying doses of P188. ACL reconstruction was then performed using an autograft from the semitendinosus tendon. Animals were euthanized 1-month following trauma, meniscal tissue was assessed for changes in morphology, mechanical properties, and proteoglycan content. Femurs and tibias were scanned using microcomputed tomography to determine changes in bone quality, architecture, and osteophyte formation. The medial meniscus experienced more damage and a decrease in the instantaneous modulus regardless of treatment group, while P188 treatment tended to limit degenerative changes in the lateral meniscus. Both lateral and medial menisci had documented decreases in the equilibrium modulus and inconsistent changes in proteoglycan content. Minimal changes were documented in the tibias and femurs, with the only significant change being the formation of osteophytes in both bones regardless of treatment group. The data suggest that P188 was able to limit some degenerative changes in the meniscus associated with PTOA and may warrant future studies.

Loosening of Posteromedial Meniscal Root Repairs Affects Knee Mechanics: A Finite Element Study.

Meniscal root repairs are susceptible to unrecoverable loosening that may displace the meniscus from the initial position reduced during surgery. Despite this, the effects of a loosened meniscal root repair on knee mechanics are unknown. We hypothesized that anatomic root repairs without loosening would restore knee mechanics to the intact condition better than loosened anatomic root repairs, but that loosened repairs would restore mechanics better than untreated meniscal root tears. Finite element knee models were used to evaluate changes in cartilage and meniscus mechanics due to repair loosening. The mechanical response from loosened anatomic root repairs was compared to anatomic repairs without loosening and untreated root tears. All conditions were evaluated at three flexion angles, 0 deg, 30 deg, and 60 deg, and a compressive force of 1000 N to simulate return-to-activity loading. The two-simple suture method was represented within the models to simulate posteromedial meniscal root repairs and the loosening of repairs was derived from previous biomechanical experimental data. Loosening decreased hoop stresses throughout the meniscus, increased posterior extrusion, and shifted loading through the meniscus-cartilage region to the cartilage-cartilage region compared to the anatomic root repair without loosening. Despite differences between repairs and loosened repairs, the changes from loosened repairs more closely resembled the anatomic repair without loosening than the untreated root repair condition. Therefore, meniscal root repairs are susceptible to loosening that will prevent a successful initial repair from remaining in the intended position and will alter cartilage and meniscus mechanics, although repairs that loosen appear better than leaving tears untreated.

The Effect of Anterior Cruciate Ligament Reconstruction with an Electropsun Scaffold on Tibiofemoral Contact Mechanics.

Surgical reconstruction of the torn ACL is performed to restore native contact mechanics. Drawbacks to traditional ACL repair techniques motivate the development of a tissue engineered ACL scaffold. Our group has developed a hierarchical electrospun polycaprolactone (PCL) scaffold that consists of rolled nanofiber bundles attached at each end with solvent-case blocks of PCL. The goal of this study was to compare ovine cadaver tibiofemoral contact mechanics after ACL reconstruction with the electrospun scaffold to a clinically applicable ACL reconstruction with a soft tissue graft and the ACL transected condition (ACLX). In the ACLX group and after ACL reconstruction with either the electrospun scaffold or soft tissue graft, pressure sensors were inserted under the menisci. Loads up to 890 N were applied at various flexion angles. The scaffold performed the best at restoring contact mechanics in the medial hemijoint to that of the native ACL. The scaffold was good at maintaining a medial-lateral balance of pressures as in the native joint whereas the ACLX shifted pressure off the lateral and on to the medial hemijoint. While the ACL scaffold didn't restore mechanics to that of the native condition, it improved contact mechanics compared to the standard graft replacement and ACLX condition.

Assessment of changes in the meniscus and subchondral bone in a novel closed-joint impact and surgical reconstruction lapine model.

Despite reconstruction surgery to repair a torn anterior cruciate ligament (ACL), patients often still show signs of post-traumatic osteoarthritis (PTOA) years following the procedure. The goal of this study was to document changes in the meniscus and subchondral bone due to closed-joint impact and surgical reconstruction in a lapine model. Animals received insult to the joint followed by surgical reconstruction of the ACL and partial meniscectomy. Following euthanasia of the animals at 1, 3, and 6-months post-impact, meniscal tissue was assessed for changes in morphology, mechanical properties and proteoglycan content. Femurs and tibias were scanned via micro-computed tomography to determine changes in bone quality, morphometry, and formation of osteophytes. Both the lateral and medial menisci showed severe degradation and tearing at all-time points, with higher degree of degeneration being observed at 6-months. Decreases in both the instantaneous and equilibrium modulus were documented in both menisci. Minimal changes were found in bone quality and morphometry, with most change documented in the tibia. Bones from the reconstructed limbs showed large volumes of osteophyte formations, with an increase in volume over time. The initial changes that were representative of PTOA may have been limited to the meniscus, but at later time points consistent changes due to the disease were seen in both tissues. This study, which builds on a previous study by this laboratory, suggests that the addition of surgical reconstruction of the ACL to our model was not sufficient to prevent the development of PTOA.

A single dose of P188 prevents cell death in meniscal explants following impact injury.

OBJECTIVE: To determine the efficacy of single and multiple administrations of Poloxamer 188 (P188) in saving meniscal cells following an injurious impact. METHODS: Meniscal explants were harvested from both the lateral and medial menisci of Flemish Giant rabbits. After a 24-h incubation period, explants were subjected to 50% impact strain to simulate traumatic joint injury, and the explants were then placed in media with or without supplemented P188. Temporal administrations of P188 over a 14-day period were given based on one of 6 different treatments regimes. Over the 14-day period, explants were cyclically loaded to 10% strain at 1 Hz for 1 h per day, five days a week. Cell viability was assessed on day 14, with the remainder of the tissue being fixed to determine cell apoptosis levels and proteoglycan changes via histology. RESULTS: The injurious impact proved to produce significant levels of cell death in meniscal explants. The ability of P188 to prevent cell death was not affected by the number of P188 doses (single versus multiple). P188 treatment proved to maintain cell viability levels comparable to those from unimpacted explants. There were no significant changes in cell apoptosis or proteoglycan coverage in the tissues over a 14-day period for any group, all treatment groups were statistically similar to the unimpacted explants. CONCLUSION: A single dose of P188 following impact is all that is necessary to inhibit cell death in the meniscus following a traumatic impact. Thus, orthopaedic surgeons may choose to administer P188 in addition to treating any other acute damage due to a traumatic load to the knee, such as anterior cruciate ligament rupture, although more in depth in vivo studies are necessary.

Nonanatomic Placement of Posteromedial Meniscal Root Repairs: A Finite Element Study.

Nonanatomic placement of posteromedial meniscal root repairs alters knee mechanics; however, little is known about how the position and magnitude of misplacement affect knee mechanics. Finite element knee models were developed to assess changes in cartilage and meniscus mechanics for anatomic and various nonanatomic repairs with respect to intact. In total, 25 different repair locations were assessed at loads of 500 N and 1000 N. The two-simple-suture method was represented within the models to simulate posteromedial meniscal root repairs. Anatomic repairs nearly restored total contact area; however, meniscal hoop stress decreased, meniscal extrusion increased, and cartilage-cartilage contact area increased. Repairs positioned further posterior altered knee mechanics the most and repairs positioned further anterior restored knee mechanics for posteromedial root repairs. Despite this, repair tension increased with further anterior placement. Anterior placement of repairs results in more restorative contact mechanics than posterior placement; however, anterior placement also increased the risk of suture cut-out or failure following repairs. Anatomic placement of repairs remains the best option because of the risks involved with anterior placement; however, suture methods need to be improved to better restore the strength of repairs to that of the native insertion. Proper placement of repairs is important to consider with meniscal root repairs because misplacement may negatively affect cartilage and meniscus mechanics in patients.

CAD/CAE of Jaipur foot for standardized and contemporary manufacturing.

Objective: Despite immense popularity of Jaipur foot as low cost prosthetic, not much work has been reported on its design for manufacturing standardization. Without manufacturing standardization, it cannot be mass produced using contemporary manufacturing technologies. The objective of this work is to carry out its computer aided design (CAD) followed by computer aided engineering (CAE) based on the material properties obtained from the previous work [1] of the authors. This may lead to the possible use of modern manufacturing processes for the Jaipur foot design.Design: After modelling using CAD tool including its organic surfaces, the designed foot was analysed using a CAE tool for balanced standing load conditions to determine maximum stresses and deformation in its various parts. The bending analysis was done to check the dorsiflexion movement so that the strained sections could be identified for more reliable and durable prosthetic foot. For the static load analysis, base of the foot was constrained and 300-500 N load was applied through the bolt whereas for bending, the part near the bolt was fixed and pressure was applied at junction of front foot and toes.Results: The results show that the maximum stress and deformation occur at the bolt, while the skin undergoes maximum strain. CAE analysis also proves the robustness of the Jaipur foot design and a well manufactured Jaipur foot as per standardized design should be able to withstand the real life conditions without failure. The CAD model is also used for FDM based printing for a nonfunctional prototype of Jaipur foot.Implications for rehabilitationThe results of this study will serve as an important guideline for further research regarding equivalent material replacement, material optimization and obtaining an optimized design after studying the foot for dynamic analysis.

Loosening of Transtibial Pullout Meniscal Root Repairs due to Simulated Rehabilitation Is Unrecoverable: A Biomechanical Study.

PURPOSE: To determine whether meniscal root repairs recover from displacement due to rehabilitative loading. METHODS: Transtibial pullout repairs of the posteromedial meniscal root were performed in 16 cadaveric ovine knees. Single- and double-tunnel repairs using the 2-simple suture technique were cyclically loaded in tension to 10,000 cycles, allowed to rest, and loaded in tension again. Paired differences in displacement with rest were recorded to evaluate recoverability. Displacement of repairs at cycles of interest was recorded, and the response of repairs to 10,000 cycles was assessed. RESULTS: All outcomes were not significantly different between the single- and double-tunnel techniques; therefore, the results were pooled. The difference in displacement between the first cycle and the first cycle after rest was 1.59 ± 0.69 mm. Repair displacement did not reach an equilibrium within 10,000 cycles and instead resulted in a steady increase in displacement of 0.05 ± 0.02 mm per additional 1,000 cycles. Sutures macroscopically began to cut out of the meniscus in both single- and double-tunnel repairs. CONCLUSIONS: This study showed that significant, unrecoverable loosening from rehabilitative loading occurred in single- and double-tunnel meniscal root repairs. Root repairs also gradually displaced with continued loading instead of reaching an equilibrium displacement after 10,000 cycles. This progressive, unrecoverable loosening needs to be studied further to better understand the resultant impact on knee mechanics. In addition, the quality and quantity of meniscal root repair healing at the time of rehabilitation should be studied to determine how susceptible patients are to repair loosening. CLINICAL RELEVANCE: Rehabilitative loading caused unrecoverable and progressive loosening of root repairs, showing the importance of healing before loading. Investigations on the effects of loosening on mechanics and the quality of repair healing at weight bearing are necessary to better understand the clinical implications.

Mechanical properties of a hierarchical electrospun scaffold for ovine anterior cruciate ligament replacement.

The anterior cruciate ligament (ACL) acts to stabilize the knee and prevent excessive motion of the tibia relative to the femur. Tears of the ACL are common and can result in pain and damage to surrounding tissues. Thus a torn ACL is often surgically replaced with an autograft or allograft material. Drawbacks to clinically available ACL grafts motivate the development of a tissue engineered ACL replacement. Our group has previously developed a polycaprolactone electrospun scaffold that mimics the hierarchical structure of the ACL. The goal of this study was to investigate the mechanical properties of the electrospun scaffold as an ACL replacement. Scaffold mechanical properties were assessed prior to implantation via stress relaxation and pull to failure testing. Following in vitro characterization, electrospun scaffolds and soft tissue grafts were implanted into ovine cadaver stifle joints as ACL replacements. Stifle joints with ACL replacements were tested via a simulated anterior drawer test as well as in situ stress relaxation and pull to failure tests and compared to stifle joints with the native ACL intact. Prior to implantation the scaffold matched the native ovine ACL well in the range of functional strains as evidenced by stress relaxation measures and the toe region stiffness. After implantation the scaffold was more similar to the native ACL than the soft tissue graft, particularly when it came to reducing joint laxity and matching stress relaxation measures. These results demonstrate that the electrospun scaffold has the potential to be a suitable material for ACL replacement. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:421-430, 2019.

Modeling Skeletal Muscle Stress and Intramuscular Pressure: A Whole Muscle Active-Passive Approach.

Clinical treatments of skeletal muscle weakness are hindered by a lack of an approach to evaluate individual muscle force. Intramuscular pressure (IMP) has shown a correlation to muscle force in vivo, but patient to patient and muscle to muscle variability results in difficulty of utilizing IMP to estimate muscle force. The goal of this work was to develop a finite element model of whole skeletal muscle that can predict IMP under passive and active conditions to further investigate the mechanisms of IMP variability. A previously validated hypervisco-poroelastic constitutive approach was modified to incorporate muscle activation through an inhomogeneous geometry. Model parameters were optimized to fit model stress to experimental data, and the resulting model fluid pressurization data were utilized for validation. Model fitting was excellent (root-mean-square error or RMSE <1.5 kPa for passive and active conditions), and IMP predictive capability was strong for both passive (RMSE 3.5 mmHg) and active (RMSE 10 mmHg at in vivo lengths) conditions. Additionally, model fluid pressure was affected by length under isometric conditions, as increases in stretch yielded decreases in fluid pressurization following a contraction, resulting from counteracting Poisson effects. Model pressure also varied spatially, with the highest gradients located near aponeuroses. These findings may explain variability of in vivo IMP measurements in the clinic, and thus help reduce this variability in future studies. Further development of this model to include isotonic contractions and muscle weakness would greatly benefit this work.

A Hydrogel Meniscal Replacement: Knee Joint Pressure and Distribution in an Ovine Model Compared to Native Tissue.

Pressure distribution of the native ovine knee meniscus was compared to a medial meniscectomy and three treatment conditions including a suture reattachment of the native tissue, an allograft, and a novel thermoplastic elastomer hydrogel (TPE) construct. The objective of this study was to assess the efficacy of a novel TPE hydrogel construct at restoring joint pressure and distribution. Limbs were loaded in uniaxial compression at 45°, 60°, and 75° flexion and from 0 to 181 kg. The medial meniscectomy decreased contact area by approximately 50% and doubled the mean and maximum pressure reading for the medial hemijoint. No treatment condition tested within this study was able to fully restore medial joint contact area and pressures to the native condition. A decrease in lateral contact area and increase in pressures with the meniscectomy was also seen; and to some degree, all reattachment and replacement conditions including the novel TPE hydrogel replacement helped to restore lateral pressures. Although the TPE construct did not perform as well as hoped in the medial compartment, it performed as well as, if not better, than the other reattachment and replacement options in the lateral. Further work is necessary to determine the best anchoring and attachment methods.

Mechanical viability of a thermoplastic elastomer hydrogel as a soft tissue replacement material.

Hydrogels are a class of synthetic biomaterials composed of a polymer network that swells with water and as such they have both an elastic and viscous component making them ideal for soft tissue applications. This study characterizes the compressive, tensile, and shear properties of a thermoplastic elastomer (TPE) hydrogel and compares the results to published literature values for soft tissues such as articular cartilage, the knee meniscus, and intervertebral disc components. The results show the TPE hydrogel material is viscoelastic, strain rate dependent, has similar surface and bulk properties, displays minimal damping under dynamic load, and has tension-compression asymmetry. When compared to other soft tissues it has a comparable equilibrium compressive modulus of approximately 0.5MPa and shear modulus of 0.2MPa. With a tensile modulus of only 0.2MPa though, the TPE hydrogel is inferior in tension to most collagen based soft tissues. Additional steps may be necessary to reinforce the hydrogel system and increase tensile modulus depending on the desired soft tissue application. It can be concluded that this material could be a viable option for soft tissue replacements.

Epidemiological study of failures of the Jaipur Foot.

OBJECTIVE: The purpose of this study was to examine effects of usage and demographics on damage to the Jaipur Foot prosthesis as well as the epidemiology and etiology of amputations performed at Santokba Durlabjhi Memorial Hospital (SDMH) in Jaipur, India. DESIGN: Total time spent standing, total time spent wearing and total distance walked were compared against severity and location of damage to the prosthesis. Time between initial fitting and follow-up visit for damaged prosthetic was also considered in this analysis. A novel damage severity scale based on prosthesis functionality is presented along with a damage location legend. RESULTS: Patients from 10 different states and two territories throughout India were included in the study. No main effects were found to be statistically significant in predicting severity or location of damage. Only the interaction between a patient's total time spent standing and their total time spent wearing the prosthesis as well as the interaction between a patient's total time spent standing and total distance walked was significant in predicting location of damage to the Jaipur Foot (p = .0327, p = .0278, respectively). CONCLUSIONS: The lack of significant usage factor effect on damage severity or location could support previous findings that lack standardization in materials and manufacturing processes, which is the major drawback of the Jaipur Foot. Implications for Rehabilitation The Jaipur Foot is a safe, reliable and stable product as no abrupt breakage or sudden falls causing injury to the patient were noted. Hence, it is a safe rehabilitation device for lost limbs. The population can squat and sit cross-legged while wearing the prosthetic foot and it does not affect damage severity or location of damage, allowing for these activities to be performed while rehabilitating. The manufacturing of the foot needs to be standardized to improve life of foot. Total time spent standing, total time spent wearing and total distance walked were not predictive of severity or location of damage to the prosthesis, hence providing patient guidelines for activity during rehabilitation.

Nanostructure-Driven Replication of Soft Tissue Biomechanics in a Thermoplastic Elastomer Hydrogel.

Synthesis of hydrogel networks capable of accurately replicating the biomechanical demands of musculoskeletal soft tissues continues to present a formidable materials science challenge. Current systems are hampered by combinations of limited moduli at biomechanically relevant strains, inefficiencies driven by undesirable hysteresis and permanent fatigue, and recovery dynamics too slow to accommodate rapid cycling prominent in most biomechanical loading profiles. Here, we report on a novel paradigm in hydrogel design based on prefabrication of an efficient nanoscale network architecture using the melt-state self-assembly of amphiphilic block copolymers. Rigorous characterization and mechanical testing reveal that swelling of these preformed networks produces hydrogels with physiologically relevant moduli and water compositions, negligible hysteresis, subsecond elastic recovery rates, and unprecedented resistance to fatigue over hundreds of thousands of compression cycles. Furthermore, by relying only on simple thermoplastic processing to form these nanostructured networks, the synthetic complexities common to most solution-based hydrogel fabrication strategies are completely avoided.