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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.

Objective Reduced subchondral bone mass and increased remodeling are associated with early stage OA. However, the direct effect of low subchondral bone mass on the risk and severity of OA development is unclear. We sought to determine the role of low bone mass resulting from a bone-specific loss of estrogen signaling in load-induced OA development using female osteoblast-specific estrogen receptor-alpha knockout (pOC-ERαKO) mice. Methods Osteoarthritis was induced by cyclic mechanical loading applied to the left tibia of 26-week-old female pOC-ERαKO and littermate control mice at peak loads of 6.5N, 7N, or 9N for 2 weeks. Cartilage damage and thickness, osteophyte development, and joint capsule fibrosis were assessed from histological sections. Subchondral bone morphology was analyzed by microCT. The correlation between OA severity and intrinsic bone parameters was determined. Results The loss of ERα in bone resulted in an osteopenic subchondral bone phenotype, but did not directly affect cartilage health. Following two weeks of cyclic tibial loading to induce OA pathology, pOC-ERαKO mice developed more severe cartilage damage, larger osteophytes, and greater joint capsule fibrosis compared to littermate controls. Intrinsic bone parameters negatively correlated with measures of OA severity in loaded limbs. Conclusions Subchondral bone osteopenia resulting from bone-specific loss of estrogen signaling was associated with increased severity of load-induced OA pathology, suggesting that reduced subchondral bone mass directly exacerbates load-induced OA development. Bone-specific changes associated with estrogen loss may contribute to the increased incidence of OA in post-menopausal women.

Mechanical loading is an anabolic stimulus that increases bone mass, and thus a promising method to counteract osteoporosis-related bone loss. The mechanism of this anabolism remains unclear, and needs to be established for both cortical and cancellous envelopes individually. We hypothesized that cortical and cancellous bone display different gene expression profiles at baseline and in response to mechanical loading. To test this hypothesis, the left tibiae of 10-week-old female C57Bl/6 mice were subjected to one session of axial tibial compression (9N, 1200 cycles, 4Hz triangle waveform) and euthanized 3 and 24 hours following loading. The right limb served as the contralateral control. We performed RNA-seq on marrow-free metaphyseal samples from the cortical shell and the cancellous core to determine differential gene expression at baseline (control limb) and in response to load. Differential expression was verified with qPCR. Cortical and cancellous bone exhibited distinctly different transcriptional profiles basally and in response to mechanical loading. More genes were differentially expressed with loading at 24 hours with more genes downregulated at 24 hours than at 3 hours in both tissues. Enhanced Wnt signaling dominated the response in cortical bone at 3 and 24 hours, but in cancellous bone only at 3 hours. In cancellous bone at 24 hours many muscle-related genes were downregulated. These findings reveal key differences between cortical and cancellous genetic regulation in response to mechanical loading. Future studies at different time points and multiple loading sessions will add to our knowledge of cortical and cancellous mechanotransduction with the potential to identify new targets for mouse genetic knockout studies and drugs to treat osteoporosis.

Estrogen receptor alpha (ERα) has been implicated in bone's response to mechanical loading in both males and females. ERα in osteoblast lineage cells is important for determining bone mass, but results depend on animal sex and the cellular stage at which ERα is deleted. We demonstrated previously that when ERα is deleted from mature osteoblasts and osteocytes in mixed-background female mice, bone mass and strength are decreased. However, few studies exist examining the skeletal response to loading in bone cell–specific ERαKO mice. Therefore, we crossed ERα floxed (ERαfl/fl) and osteocalcin-Cre (OC-Cre) mice to generate animals lacking ERα in mature osteoblasts and osteocytes (pOC-ERαKO) and littermate controls (LC). At 10 weeks of age, the left tibia was loaded in vivo for 2 weeks. We analyzed bone mass through micro-CT, bone formation rate by dynamic histomorphometry, bone strength from mechanical testing, and osteoblast and osteoclast activity by serum chemistry and immunohistochemistry. ERα in mature osteoblasts differentially regulated bone mass in males and females. Compared with LC, female pOC-ERαKO mice had decreased cortical and cancellous bone mass, whereas male pOC-ERαKO mice had equal or greater bone mass than LC. Bone mass results correlated with decreased compressive strength in pOC-ERαKO female L5 vertebrae and with increased maximum moment in pOC-ERαKO male femora. Female pOC-ERαKO mice responded more to mechanical loading, whereas the response of pOC-ERαKO male animals was similar to their littermate controls. © 2015 American Society for Bone and Mineral Research. © 2015 American Society for Bone and Mineral Research.

Sclerostin, encoded by the Sost gene, is an important negative regulator of bone formation that has been proposed to have a key role in regulating the response to mechanical loading. To investigate the effect of long-term Sclerostin deficiency on mechanotransduction in bone, we performed experiments on unloaded or loaded tibiae of 10 week old female Sost−/− and wild type mice. Unloading was induced via 0.5U botulinum toxin (BTX) injections into the right quadriceps and calf muscles, causing muscle paralysis and limb disuse. On a separate group of mice, increased loading was performed on the left tibiae through unilateral cyclic axial compression of equivalent strains (+1200 µe) at 1200 cycles/day, 5 days/week. Another cohort of mice receiving equivalent loads (−9.0 N) also were assessed. Contralateral tibiae served as normal load controls. Loaded/unloaded and normal load tibiae were assessed at day 14 for bone volume (BV) and formation changes. Loss of BV was seen in the unloaded tibiae of wild type mice, but BV was not different between normal load and unloaded Sost−/− tibiae. An increase in BV was seen in the loaded tibiae of wild type and Sost−/− mice over their normal load controls. The increased BV was associated with significantly increased mid-shaft periosteal mineralizing surface/bone surface (MS/BS), mineral apposition rate (MAR), and bone formation rate/bone surface (BFR/BS), and endosteal MAR and BFR/BS. Notably, loading induced a greater increase in periosteal MAR and BFR/BS in Sost−/− mice than in wild type controls. Thus, long-term Sclerostin deficiency inhibits the bone loss normally induced with decreased mechanical load, but it can augment the increase in bone formation with increased load. © 2014 American Society for Bone and Mineral Research.

Reduced bioavailability of estrogen increases skeletal fracture risk in postmenopausal women, but the mechanisms by which estrogen regulates bone mass are incompletely understood. Because estrogen signaling in bone acts, in part, through estrogen receptor alpha (ERα), mice with global deletion of ERα (ERαKO) have been used to determine the role of estrogen signaling in bone biology. These animals, however, have confounding systemic effects arising from other organs, such as increased estrogen and decreased insulin-like growth factor 1 (IGF-1) serum levels, which may independently affect bone. Mice with tissue-specific ERα deletion in chondrocytes, osteoblasts, osteocytes, or osteoclasts lack the systemic effects seen in the global knockout, but show that presence of the receptor is important for the function of each cell type. Although bone mass is reduced when ERα is deleted from osteoblasts, no study has determined if this approach reduces whole bone strength. To address this issue, we generated female osteoblast-specific ERαKO mice (pOC-ERαKO) by crossing mice expressing a floxed ERα gene (ERα(fl/fl)) with mice transgenic for the osteocalcin-Cre promoter (OC-Cre). Having confirmed that serum levels of estrogen and IGF-1 were unaltered, we focused on relating bone mechanics to skeletal phenotype using whole bone mechanical testing, microcomputed tomography, histology, and dynamic histomorphometry. At 12 and 18 weeks of age, pOC-ERαKO mice had decreased cancellous bone mass in the proximal tibia, vertebra, and distal femur, and decreased cortical bone mass in the tibial midshaft, distal femoral cortex, and L5 vertebral cortex. Osteoblast activity was reduced in cancellous bone of the proximal tibia, but osteoclast number was unaffected. Both femora and vertebrae had decreased whole bone strength in mechanical tests to failure, indicating that ERα in osteoblasts is required for appropriate bone mass and strength accrual in female mice. This pOC-ERαKO mouse is an important animal model that could enhance our understanding of estrogen signaling in bone cells in vivo.

Enhancing the quantity and quality of cancellous bone with anabolic pharmacologic agents may lead to more successful outcomes of non-cemented joint replacements. Using a novel rabbit model of cancellous bone loading, we examined two specific questions regarding bone formation at the bone-implant interface: (1) does the administration of intermittent PTH, a potent anabolic agent, and mechanical loading individually and combined enhance the peri-implant cancellous bone volume fraction; and, (2) does surgical trauma enhance the anabolic effect of PTH on peri-implant bone volume fraction. In this model, PTH enhanced peri-implant bone volume fraction by 30% in loaded bone, while mechanical loading alone increased bone volume fraction modestly (+10%). Combined mechanical loading and PTH treatment had no synergistic effect on any cancellous parameters. However, a strong combined effect was found in bone volume fraction with combined surgery and PTH treatment (+34%) compared to intact control limbs. Adaptive changes in the cancellous bone tissue included increased ultimate stress and enhanced remodeling activity. The number of proliferative osteoblasts increased as did their expression of pro-collagen 1 and PTH receptor 1, and the number of TRAP positive osteoclasts also increased. In summary, both loading and intermittent PTH treatment enhanced peri-implant bone volume, and surgery and PTH treatment had a strong combined effect. This finding is of clinical importance since enhancing early osseointegration in the post-surgical period has numerous potential benefits.

The tibial post in posterior-stabilized total knees is a potential source of polyethylene wear debris, but the relationship between the shape and location of the tibial post in relation to the tibiofemoral bearing surfaces and the subsequent wear damage patterns remains unknown.We used observations made on retrieved implant components from three contemporary posterior-stabilized knee designs to examine how differences in tibial post design affected wear damage on the post.We examined 113 retrieved Zimmer NexGen(®), 103 Exactech Optetrak(®), and 58 Smith and Nephew Genesis(®) II posterior-stabilized inserts using a subjective scale to grade post damage.All 274 inserts demonstrated wear damage. Total wear scores and scores for wear damage on the anterior post differed among designs: Optetrak(®) 20 ± 4 and 5 ± 1, NexGen(®) 13 ± 4 and 3 ± 1, and Genesis(®) II 8 ± 3 and 1 ± 1, respectively. The Optetrak(®) had predominantly anterior wear damage, the NexGen(®) had more global wear damage, and the Genesis(®) II had predominantly posterior wear damage. Tibial post wear damage and anterior post wear damage were primarily determined by implant design and to a lesser extent by length of implantation and revision diagnosis.Although tibial post wear damage is multifactorial, the primary determinant of wear damage, and specifically anterior wear damage, is implant design.The constraint provided by the posterior-stabilized post-cam contact in modern knee arthroplasties is reflected in the wear damage patterns that occur during in vivo use. Unintended constraint such as anterior impingement should be addressed through design modifications for future posterior-stabilized knee arthroplasties.

Mobile-bearing TKAs reportedly have no clinical superiority over fixed-bearing TKAs, but a potential benefit is improved polyethylene wear behavior.We asked whether extent of damage and wear patterns would be less severe on retrieved mobile-bearing TKAs than on fixed-bearing TKAs and if correlations with patient demographics could explain differences in extent or locations of damage.We performed damage grading and mapping of 48 mobile-bearing TKAs retrieved due to osteolysis/loosening, infection, stiffness, instability or malpositioning. Visual grading used stereomicroscopy to identify damage, and a grade was assigned based on extent and severity. Each damage mode was then mapped onto a photograph of the implant surface, and the area affected was calculated.Marked wear damage occurred on both surfaces, with burnishing, scratching, and pitting the dominant modes. Damage occurred over a large portion of both surfaces, exceeding the available articular borders in nearly 30% of implants. Wear of mobile-bearing surfaces included marked third-body debris. Damage on tibiofemoral and mobile-bearing surfaces was not correlated with patient BMI or component alignment. Damage on mobile-bearing surfaces was positively correlated with length of implantation and was greater in implants removed for osteolysis or instability than in those removed for stiffness or infection.Each bearing surface in mobile-bearing implants was damaged to an extent similar to that in fixed-bearing implants, making the combined damage score higher than that for fixed-bearing implants. Mobile-bearing TKAs did not improve wear damage, providing another argument against the superiority of these implants over fixed-bearing implants.

Unicondylar knee arthroplasty (UKA) is considered an alternative to total knee arthroplasty for patients who have arthritis limited to one compartment of the knee. This study examined surface damage of 3 contemporary UKA designs that were retrieved at revision surgery. Two of the UKA designs were fixed bearing and one was mobile bearing. Demographic information was collected, as well as information about the implants used at revision surgery. Articular surface damage was greater in the fixed-bearing designs as compared to the mobile bearing, although the mobile-bearing implants had significantly shorter length of implantation. Backside damage was also graded for the mobile bearing and when combined with articular wear resulted in overall damage scores higher than both fixed-bearing designs. The fixed-bearing designs showed delamination and surface deformation, whereas the mobile bearing had no evidence of these damage modes. However, mobile-bearing components showed other types of wear, and significant wear damage was present on the bearing surfaces of the mobile-bearing implants despite a short time of implantation. At the time of conversion to a total knee arthroplasty, more than 50% of cases required the use of stems, augments, or constrained inserts for the tibial reconstruction. In conclusion, wear modes differed among UKA prosthesis designs. Revision of a UKA to a total knee arthroplasty remains complex with the tibial preparation more complicated than in the primary setting.

Background: The menisci are integral to normal knee function. The purpose of this study was to measure the contact pressures transmitted to the medial tibial plateau under physiological loads as a function of the percentage of the meniscus involved by the radial tear or repair. Our hypotheses were that (1) there is a threshold size of radial tears above which contact mechanics are adversely affected, and (2) partial meniscectomy results in increased contact pressure compared with that found after meniscal repair. Methods: A knee simulator was used to apply physiological multidirectional dynamic gait loads across human cadaver knees. A sensor inserted below the medial meniscus recorded contact pressures in association with (1) an intact meniscus, (2) a radial tear involving 30% of the meniscal rim width, (3) a radial tear involving 60% of the width, (4) a radial tear involving 90% of the width, (5) an inside-out repair with horizontal mattress sutures, and (6) a partial meniscectomy. The effects of these different types of meniscal manipulation on the magnitude and location of the peak contact pressure were assessed at 14% and 45% of the gait cycle. Results: The peak tibial contact pressure in the intact knees was 6 ± 0.5 MPa and 7.4 ± 0.6 MPa at 14% and 45% of the gait cycle, respectively. The magnitude and location of the peak contact pressure were not affected by radial tears involving up to 60% of the meniscal rim width. Radial tears involving 90% resulted in a posterocentral shift in peak-pressure location manifested by an increase in pressure in that quadrant of 1.3 ± 0.5 MPa at 14% of the gait cycle relative to the intact condition. Inside-out mattress suture repair of a 90% tear did not restore the location of the pressure peak to that of the intact knee. Partial meniscectomy led to a further increase in contact pressure in the posterocentral quadrant of 1.4 ± 0.7 MPa at 14% of the gait cycle. Conclusions: Large radial tears of the medial meniscus are not functionally equivalent to meniscectomies; the residual meniscus continues to provide some load transmission and distribution functions across the joint. Clinical Relevance: The results of this study support meniscal preservation and repair of medial radial tears.

Despite the large loads placed upon constrained acetabular liners, little is known of their mechanical performance. We analyzed retrieved liners to determine wear and other damage modes and assess associations between types and severity of damage and clinical, radiographic, and implant variables. Outer rim impingement frequency and severity were higher than that for the inner rim. The 20 degrees elevation was most frequently affected by impingement. Inner rim impingement was more frequent with small heads. Outer bearing surface wear scores were higher than inner bearing scores. Liners removed for infection or stem failure had similar damage compared with other groups, demonstrating the complex relationship of impingement and wear with clinical performance. No association was found between liner damage and clinical and radiographic variables.

The high incidence of fragility fractures in cortico-cancellous bone locations, plus the fact that individual skeletal sites exhibit different responsiveness to load and disease, emphasizes the need to document separately gene expression in cortical and cancellous bone. A further confounding factor is marrow contamination since its high cellularity may effect gene expression measurements. We isolated RNA from cortical and cancellous bone of intact mouse tibiae, and also after marrow removal by flushing or centrifugation. RNA isolated from cancellous bone by each method was sufficient for gene expression analysis. Centrifugation removed contaminating cells more efficiently than flushing, as indexed by histology and decreased expression of Icam4, a highly expressed erythroid gene. In contrast, centrifuged cortical bone had 12- and 13- fold higher expression of the bone-related genes Col1a1 and Bglap, while levels in marrow-free cancellous bone were 30- and 31-fold higher when compared to bone where marrow was left intact. Furthermore, cortical bone had higher expression of Col1a1 and Bglap than cancellous bone. Thus, RNA isolated by this novel approach can reveal site-specific changes in gene expression in cortical and cancellous bone sites.

Highly crosslinked UHMWPE is associated with increased wear resistance in hip simulator and clinical studies. Laboratory and case studies, however, have described rim fracture in crosslinked acetabular liners. Controversy exists, therefore, on the relative merits of crosslinked liners over conventional liners in terms of wear performance versus resistance to fatigue cracking.We asked whether crosslinked liners would show less surface damage than conventional liners but would be more susceptible to fatigue damage.We examined 36 conventional UHMWPE and 39 crosslinked UHMWPE retrieved implants with similar patient demographics and identical design for evidence of wear damage, including articular surface damage, impingement, screw-hole creep, and rim cracks.We observed no difference in wear damage scores for the two liners. Conventional liners more frequently impinged but were more often elevated with smaller head sizes. We observed creep in approximately 70% of both types of liners. Incipient rim cracks were found in five crosslinked liners, and one liner had a rim fracture. Only one conventional liner had an incipient rim crack.Contrary to our expectation, damage was similar between crosslinked and conventional UHMWPE liners. Moreover, the 15% occurrence (six of 39) of incipient or complete fractures in crosslinked liners as compared with a 3% occurrence (one of 36) in conventional liners may have implications for the long-term performance of crosslinked liners. Longer-term studies will be necessary to establish the fate of rim cracks and thus the overall clinical fatigue performance of crosslinked liners.

Oxidized zirconium (OxZr) was introduced to serve as a ceramic surface for femoral components in TKA. The aim of this study was to compare retrieved OxZr components and corresponding PE inserts in matched comparison with conventional cobalt/chrome/molybdenum alloy (CoCrMo). Eleven retrieved posterior stabilized TKA with an OxZr femoral component were included. This included 6 implants from an earlier preliminary study. From a cohort of 56 retrieved TKA with conventional CoCrMo femoral components, pairs were matched according to duration of implantation, patient age, reason for revision, and BMI. Polyethylene inlays and femoral components were optically scored for in vivo damage. The average damage score of the tibial PE inserts was significantly lower with OxZr components (p=0.01). Mainly burnishing and scratches were found. The average wear score in the visual analysis of the femoral components was significantly lower for the OxZr as well (p=0.005). Femoral components made of OxZr were less sensitive to in vivo damage and corresponding PE inlays also showed less damage than CoCrMo components.