Validation of electronic administration of knee surveys among ACL-injured patients.

PURPOSE: Knee-specific patient reported outcome measures (PROMs) are important tools in evaluating the effectiveness of sports medicine interventions. The PROMs were originally developed for paper administration, but electronic data capture technologies offer potential benefits such as increased efficiency and accuracy. The aim of this study was to assess the validity of touch screen versus paper administration using several common knee-specific and general health surveys. METHODS: Agreement between scores was compared for knee-specific PROMs administered on paper versus computer; paper versus tablet; computer versus tablet in 60 patients per group undergoing ACL reconstruction. Surveys were given at pre-operative assessment and between 1 and 7 days later. Weighted kappa statistic (κ) and intraclass correlation coefficients (ICC) were calculated to test agreement between the two modalities in: IKDC Subjective Knee Form, Marx Activity Scale, Tegner Activity Level Scale, and Lysholm Knee Scale. SF-12 Physical and Mental Component Summary scores were also assessed. RESULTS: Response rate was over 90 %. Mean age was 29.6 ± 10.9 years, with patients in the paper-computer cohort being 4 years older than in the other groups. Agreement was substantial or better for all PROMs collected: IKDC Subjective (ICC: 0.79); Marx (ICC: 0.70); Lysholm (ICC: 0.65); and Tegner (κ = 0.67). Agreement for the SF-12 PCS (ICC: 0.77) and MCS (ICC: 0.73) was also found to have substantial agreement. CONCLUSION: In conclusion, touch screen-based PROMs are a valid capture method, providing reliable results relative to traditional paper survey administration. Digital methods of direct data capture may also foster multi-centre collaborations and allow for more accurate comparisons of outcomes between patient groups in clinical practice and orthopaedic research. LEVEL OF EVIDENCE: II.

Patient-Reported Outcome Measures-What Data Do We Really Need?

The Center for Medicaid and Medicare Services has recently announced the inclusion of several patient-reported outcome measures (PROMs), including the abbreviated Hip Disability and Osteoarthritis Outcome Score and Knee Injury and Osteoarthritis Outcome Score for joint replacement (HOOS, JR and KOOS, JR) for the purpose of quality assessment in total hip and total knee replacement (THR and TKR). Historically, Center for Medicaid and Medicare Services and other agencies have used measures of process (eg, % vaccinated) or adverse events (eg, infection rates, readmission rates) for quality assessment. However, the use of PROMs has become a priority based on stated goals by the National Quality Strategy and Institute of Medicine for a more patient-centered approach. Here, we review several general health and joint-specific PROMs, which have been extensively used in research to assess treatment efficacy and discuss their relevance to the new criteria for quality assessment, particularly for THR and TKR. Although we expect HOOS, JR and KOOS, JR to yield much useful information in the near term, these surveys are likely an interim solution. In the future, we anticipate that novel measurement platforms, such as wearable technologies or patient-specific surveys, may open new and exciting avenues of research to discover which types of data-perhaps not previously available-best represent patient quality of life and satisfaction after THR, TKR, or other orthopedic procedures.

Patient Selection in Randomized Controlled Trials of Total Knee Arthroplasty: A Systematic Review Assessing Inclusion Criteria.

BACKGROUND: Patients undergo total knee arthroplasty (TKA) at widely disparate stages of osteoarthritis, raising the possibility of high heterogeneity among patients enrolled in TKA research studies. Obscuration of treatment effectiveness and other problems that may stem from cohort heterogeneity can be controlled in clinical studies by rigorously defining target patients. The purpose of this review was to determine the extent to which randomized controlled trials (RCTs) on TKA use osteoarthritis severity, as defined by radiographic grade or patient-reported outcome measures (PROMs), in their inclusion criteria, and to investigate potential impact on outcome. METHODS: A search of PubMed, Embase, Scopus, Web of Science, and Cochrane databases used a combination of terms involving TKA, PROMs, and radiographic scoring. A total of 1,227 studies were independently reviewed by 2 screeners for the above terms. RCTs with ≥100 patients (236) and with <100 patients (325) undergoing TKA were analyzed with regard to the specific inclusion criteria and recruitment process. RESULTS: Among the identified RCTs with ≥100 patients, 18 (<8%, with a total of 2,952 randomized patients) used specific radiographic scoring or PROM thresholds in their inclusion criteria. Eleven of the 18 studies used specific radiographic scoring, such as the Kellgren-Lawrence or Ahlbäck classifications. Three studies used preoperative PROM thresholds: Knee Society Knee Score of <60, Knee Society Function Score of <60, Oxford Knee Score of <20, and Hospital for Special Surgery Score of <60. Among studies with <100 patients, 48 (<15%) used specific inclusion criteria. CONCLUSIONS: The vast majority of RCTs (>85%) did not enroll patients based on disease severity, as measured by PROM score thresholds or radiographic classifications, in their inclusion criteria. The lack of consistent inclusion criteria likely results in heterogeneous cohorts, potentially undermining the validity of RCTs on TKA. LEVEL OF EVIDENCE: Prognostic Level I . See Instructions for Authors for a complete description of levels of evidence.

The Role of Constraint in Revision Total Knee Replacement for Instability: Full Component Revision Vs Isolated Polyethylene Exchange in Selected Patients.

Background: Instability is a common indication for revision after total knee arthroplasty. Replacement of multiple components is the current standard, but isolated polyethylene liner exchange (IPE) may present a less-morbid alternative. This study aims to determine (1) whether IPE results in similar rerevision frequency to component revision in select patients with symptomatic instability and (2) the effect of increasing constraint on the outcome. Methods: We retrospectively reviewed 117 patients revised for symptomatic total knee arthroplasty instability from January 2016 to December 2017. The component revision (60 patients) or IPE (57 patients) cohorts were further stratified based on whether constraint was increased or not. The primary objective was to compare rerevision rates 2 years after component revision vs IPE. The secondary objectives consisted of evaluating reasons for rerevision, preoperative and postoperative patient-reported outcome measures, and range of motion. Results: The rerevision rate was 18%, with no statistical difference between component and IPE cohorts. Cases where level of constraint increased due to revision, a significantly lower rate of rerevision was detected (9 of 77) (12%) than in cases where constraint did not increase (12 of 39) (31%) (P=0.012). This association was also noted in the component revision cohort but not in the IPE cohort (P=0.011). Conclusions: Rerevision occurred at similar frequencies 2 years after IPE or component revision for total knee arthroplasty instability. For component revision, increased constraint was associated with significantly fewer rerevisions.

Inducing Angiogenesis in the Nucleus Pulposus.

Bone morphogenetic protein (BMP) gene delivery to Lewis rat lumbar intervertebral discs (IVDs) drives bone formation anterior and external to the IVD, suggesting the IVD is inhospitable to osteogenesis. This study was designed to determine if IVD destruction with a proteoglycanase, and/or generating an IVD blood supply by gene delivery of an angiogenic growth factor, could render the IVD permissive to intra-discal BMP-driven osteogenesis and fusion. Surgical intra-discal delivery of naïve or gene-programmed cells (BMP2/BMP7 co-expressing or VEGF165 expressing) +/- purified chondroitinase-ABC (chABC) in all permutations was performed between lumbar 4/5 and L5/6 vertebrae, and radiographic, histology, and biomechanics endpoints were collected. Follow-up anti-sFlt Western blotting was performed. BMP and VEGF/BMP treatments had the highest stiffness, bone production and fusion. Bone was induced anterior to the IVD, and was not intra-discal from any treatment. chABC impaired BMP-driven osteogenesis, decreased histological staining for IVD proteoglycans, and made the IVD permissive to angiogenesis. A soluble fragment of VEGF Receptor-1 (sFlt) was liberated from the IVD matrix by incubation with chABC, suggesting dysregulation of the sFlt matrix attachment is a possible mechanism for the chABC-mediated IVD angiogenesis we observed. Based on these results, the IVD can be manipulated to foster vascular invasion, and by extension, possibly osteogenesis.

Evaluation of direct in vivo gene transfer in an equine metacarpal IV ostectomy model using an adenoviral vector encoding the bone morphogenetic protein-2 and protein-7 gene.

OBJECTIVE: To evaluate gene transfer in an equine metacarpal IV (MCIV) ostectomy model using adenoviral vectors encoding the human bone morphogenetic protein-2 and protein-7 gene (Ad-BMP-2/-7). EXPERIMENTAL ANIMALS: Healthy adult horses (n = 15). METHODS: A plate stabilized, critical size 1.5 cm ostectomy was created in left and right MCIV. The ostectomy site was injected with either Ad-green fluorescent protein (Ad-GFP) or Ad-hBMP-2/-7 at completion of surgery; the same treatment was assigned to both the left and right forelimb of each horse (n = 5 horses/group). Bone healing was evaluated radiographically every 2 weeks for 16 weeks. Horses in a pilot study (n = 5) were used as untreated controls for radiographic evaluation to 8 weeks. After euthanasia at 16 weeks bone healing was evaluated using dual energy X-ray absorptiometry (DEXA) and histomorphometry. Data were analyzed using an ANOVA or Kruskal-Wallis test. Level of significance was P < .05. RESULTS: At 4 and 6 weeks, the Ad-GFP group had a significantly lower percentage defect ossification compared with the untreated control group. There was no significant difference between untreated and Ad-hBMP-2/-7 groups at any time point and no significant difference in bone healing radiographically, histologically, or using DEXA between any groups at 16 weeks. CONCLUSIONS: Ad-hBMP-2/-7 did not improve bone healing in horses at 16 weeks.

Lumbar spine intervertebral disc gene delivery of BMPs induces anterior spine fusion in lewis rats.

Minimally invasive techniques and biological autograft alternatives such as the bone morphogenetic proteins (BMPs) can reduce morbidity associated with spinal fusions. This study was a proof-of-concept for gene-therapy-mediated anterior spine fusion that could be adapted to percutaneous technique for clinical use. Isogeneic bone marrow stromal cells genetically programmed to express b-galactosidase (LACZ, a marker gene), BMP2, BMP7, a mixture of BMP2 and BMP7 infected cells (homodimers, HM), or BMP2/7 heterodimers (HT) were implanted into the discs between lumbar vertebrae 4 and 5 (L4/5) and L5/6 of male Lewis rats. Spine stiffening was monitored at 4, 8 and 12 weeks using noninvasive-induced angular displacement (NIAD) testing. At 12 weeks isolated spines were assessed for fusion and bone formation by palpation, biomechanical testing [four-point bending stiffness, moment to failure in extension, and in vitro angular displacement (IVAD)], faxitron x-rays, microCT, and histology. Progressive loss of NIAD occurred in only the HT group (p < 0.001), and biomechanical tests correlated with the NIAD results. Significant fusion occurred only in the HT group (94% of animals with one or both levels) as assessed by palpation (p < 0.001), which predicted HT bone production assessed by faxitron (p ≤ 0.001) or microCT (p < 0.023). Intervertebral bridging bone was consistently observed only in HT-treated specimens. Induced bone was located anterior and lateral to the disc space, with no bone formation noted within the disc. Percutaneous anterior spine fusions may be possible clinically, but induction of bone inside the disc space remains a challenge.

Sonic hedgehog expands diaphyseal trabecular bone altering bone marrow niche and lymphocyte compartment.

Bone marrow contains distinct microenvironments that regulate hematopoietic stem cells (HSCs). The endosteal HSC niche includes osteoblasts, mineral, and extracellular matrix proteins that interact through various molecular signals to control HSCs. Sonic hedgehog (Shh) is a morphogen involved in the regulation of skeletal development and hematopoiesis, but the effects of Shh on bone in relation to the HSC niche are not well understood. We demonstrate that systemic overexpression of Shh in mice increases osteoblast number with the resultant formation of new trabeculae in the femoral diaphysis. Suggestive of a functional change in the hematopoietic niche, numbers of Lin(-) Sca-1(+) c-Kit(+) cells with hematopoietic progenitor function expand, although cells with in vivo repopulating capacity in the wild-type environment do not increase. Instead, Shh mediates a decrease in number of bone marrow lymphocytes accompanied by a decreased expression of stromal-derived growth factor 1 (SDF-1) and a decrease in Flk2-expressing Lin(-) Sca-1(+) c-Kit(+) cells, indicating a modulation of early lymphopoiesis. This is caused by a microenvironment-induced mechanism as Shh treatment of bone marrow recipients, but not donors, results in a dramatic depletion of lymphocytes. Together, these data suggest that Shh mediates alterations in the bone marrow hematopoietic niche affecting the early lymphoid differentiation.

In vivo and in vitro analysis of rat lumbar spine mechanics.

BACKGROUND: Rodent lumbar and caudal (tail) spine segments provide useful in vivo and in vitro models for human disc research. In vivo caudal models allow characterization of the effect of static and dynamic loads on disc mechanics of individual animals with time, but the lumbar models have required sacrifice of the animals for in vitro mechanical testing. QUESTIONS/PURPOSES: We therefore developed a novel displacement controlled in vivo lumbar spine noninvasive induced angular displacement (NIAD) test; data obtained with NIAD were used to compare angular displacement between segmental levels (L4/L5, L5/L6 and L6/S1), interobserver radiograph measurement agreement, and intraobserver radiograph measurement repeatability. Measurements from NIAD were compared with angular displacement, bending stiffness, and moment to failure measured by an in vitro test. METHODS: Anesthetized Lewis rats were xrayed in a 90° angled fixture, and NIAD was measured at lumbar levels L4 to S1 by two independent and blinded observers. After euthanasia, in vitro angular displacement (IVAD), stiffness, and failure moment were measured for the combined L4-L6 segment in four-point bending. RESULTS: NIAD was greater at L4/L5 and L5/L6 than at L6/S1. Combined coronal NIAD for L4-L6 was 42.8° ± 5.3° and for IVAD was 61.5° ± 3.8°. Reliability assessed by intraclass correlation coefficient (ICC) was 0.905 and 0.937 for intraobserver radiograph measurements, and interobserver ICCs ranged from 0.387 to 0.653 for individual levels. The interobserver ICC was 0.911 for combined data from all levels. Reliability for test-retest NIAD measurements had an ICC of 0.932. In vitro failure moment correlated with NIAD left bending. CONCLUSIONS: The NIAD method yielded reproducible and reliable rat lumbar spine angular displacement measurements without required euthanasia, and allows repetitive monitoring of animals with time. For lumbar spine research studies performed during a course of time, the NIAD method may reduce animal numbers required by providing serial angular displacement measurements without euthanasia. CLINICAL RELEVANCE: Improved methods to assess comparative models for disease or aging may permit enhanced clinical treatments and improved patient care.

Monitoring Patient Recovery After THA or TKA Using Mobile Technology.

BACKGROUND: Smartphones offer the possibility of assessing recovery of mobility after total hip or knee arthroplasty (THA or TKA) passively and reliably, as well as facilitating the collection of patient-reported outcome measures (PROMs) with greater frequency. QUESTIONS/PURPOSES: We investigated the feasibility of using mobile technology to collect daily step data and biweekly PROMs to track recovery after total joint arthroplasty. METHODS: Pre- and post-operative daily steps were recorded in prospectively enrolled patients (128 THA and 139 TKA) via an app, which uses the phone's accelerometer. During 6-month follow-up, patients also completed PROMs (the pain numeric rating scale, the Hip Disability and Osteoarthritis Outcome Score Joint Replacement [HOOS JR] and the Knee Injury and Osteoarthritis Outcome Score Joint Replacement [KOOS JR]), and HOOS or KOOS JR quality of life domain via a mobile-enabled web link. RESULTS: At least 6 months of follow-up was completed by 65% for THA and 68% for TKA patients. Reasons for non-completion included time commitment, phone battery, app issues, and health complications. Responses from 78% of requested PROMs were returned with 96% of patients returning at least one post-operative PROM. Step data were available from 92% of days from male patients and 86% of days from female patients. The most robust recovery occurred early, within the first 2 months. The groups with higher pre-operative steps were more likely to recover their maximum daily steps at an earlier time point. Correlations between step counts and PROMs scores were modest. CONCLUSION: Assessing large amounts of post-TKA and post-THA step data using mobile technology is feasible. Completion rates were good, making the technology very useful for collecting frequent PROMs. Being unable to ensure that patients always carried their phones limited our analysis of the step counts.

Crosswalks Between Knee and Hip Arthroplasty Short Forms: HOOS/KOOS JR and Oxford.

BACKGROUND: The Oxford Knee Score (OKS); Oxford Hip Score (OHS); Knee injury and Osteoarthritis Outcome Score, Joint Replacement (KOOS JR); and Hip disability and Osteoarthritis Outcome Score, Joint Replacement (HOOS JR) are well-validated and widely used short-form patient-reported outcome measures (PROMs) for assessing outcomes after total knee arthroplasty (TKA) and total hip arthroplasty (THA). We are not aware of the existence of any crosswalks to convert scores between these PROMs. We aimed to develop and validate crosswalks that will permit the comparison of scores between studies using different PROMs and the pooling of results for meta-analyses. METHODS: We retrospectively analyzed scores from patients (486 in the knee cohort and 340 in the hip cohort) from the Syracuse Orthopedic Specialists Joint Registry who had completed the appropriate PROMs (OKS and KOOS JR in the knee cohort and OHS and HOOS JR in the hip cohort) as the standard of care before undergoing primary TKA or unicompartmental knee arthroplasty (UKA) between January 9, 2016, and June 19, 2017, or primary THA or hip resurfacing between November 29, 2010, and October 30, 2017, or when returning for postoperative care. Using the equipercentile equating method, we created 4 crosswalks: OKS to KOOS JR, KOOS JR to OKS, OHS to HOOS JR, and HOOS JR to OHS. To assess validity, Spearman coefficients were calculated using bootstrapping methods, and means for actual and crosswalk-derived scores were compared. RESULTS: There were minimal differences between the means of the known and crosswalk-derived scores. As calculated with the use of bootstrapping methods, Spearman coefficients between the actual and derived scores were strong and positive for both knee arthroplasty crosswalks (0.888 to 0.889; 95% confidence interval [CI], 0.887 to 0.891) and hip arthroplasty crosswalks (0.916 to 0.918; 95% CI, 0.914 to 0.919). CONCLUSIONS: We successfully created 4 crosswalks that allow conversion of Oxford scores to KOOS and HOOS JR scores and vice versa. These crosswalks will allow harmonization of PROMs assessment regardless of which of the short forms are used, which may facilitate multicenter collaboration or allow sites to switch PROMs without loss of historic comparison data. LEVEL OF EVIDENCE: Level III. See Instructions for Authors for a complete description of levels of evidence.

Chondrogenesis, joint formation, and articular cartilage regeneration.

The repair of joint surface defects remains a clinical challenge, as articular cartilage has a limited healing response. Despite this, articular cartilage does have the capacity to grow and remodel extensively during pre- and post-natal development. As such, the elucidation of developmental mechanisms, particularly those in post-natal animals, may shed valuable light on processes that could be harnessed to develop novel approaches for articular cartilage tissue engineering and/or regeneration to treat injuries or degeneration in adult joints. Much has been learned through mouse genetics regarding the embryonic development of joints. This knowledge, as well as the less extensive available information regarding post-natal joint development is reviewed here and discussed in relation to their possible relevance to future directions in cartilage tissue repair and regeneration.

Defining the Learning Curve for Hip Arthroscopy: A Threshold Analysis of the Volume-Outcomes Relationship.

BACKGROUND: Hip arthroscopy has emerged as a successful option for the treatment of femoroacetabular impingement and related hip disorders, but the procedure is technically challenging. PURPOSE: To define the learning curve through which surgeons become proficient at hip arthroscopy. STUDY DESIGN: Cohort study; level of evidence, 3. METHODS: The authors identified hip arthroscopy procedures performed by surgeons through a New York State database (Statewide Planning and Research Cooperative System) and followed those cases for additional hip surgery (total hip arthroplasty, hip resurfacing, or ipsilateral hip arthroscopy) within 5 years of the original procedure. Career volume for each case was calculated as the number of hip arthroscopy procedures that the surgeon had performed. Volume strata were identified via the stratum-specific likelihood ratio method. A Cox proportional hazards model was used to measure the effect of surgeon career volume on risk of additional hip surgery, adjusting for the following patient characteristics: age, sex, race/ethnicity, insurance type, and concurrent diagnosis of hip osteoarthritis. RESULTS: Among 8041 hip arthroscopies performed by 251 surgeons, 989 (12.3%) cases underwent additional hip surgery within 5 years. Four strata of surgeon career volume associated with distinct frequencies of reoperation were identified: cases in the lowest stratum (0-97) had the highest frequency of additional surgery (15.4%). Frequencies declined for cases in the medium (98-388), high (389-518), and highest (≥519) strata (13.8%, 10.1%, and 2.6%, respectively). There was an increased risk of subsequent surgery in each stratum when compared with the highest stratum (hazard ratio [95% CI]: low volume, 3.22 [2.29-4.54]; medium, 3.40 [2.41-4.82]; high, 2.81 [1.86-4.25]; P < .0001 for all). Patients with a diagnosis of hip osteoarthritis had increased risk of subsequent hip arthroplasty or resurfacing (2.46 [2.09-2.89], P < .0001) . Risk also increased with age: 30 to 39 vs ≤29 years (5.12 [3.29-8.00], P < .0001), 40 to 49 vs ≤29 years (11.30 [7.43-17.190], P < .0001), ≥50 vs ≤29 years (18.39 [12.10-27.96], P < .0001). Increased age and osteoarthritis were not risk factors for revision hip arthroscopy. CONCLUSION: The learning curve for hip arthroscopy was unexpectedly demanding. Cases performed by surgeons with career volumes ≥519 had significantly lower risk of subsequent hip surgery than those performed by lower-volume surgeons.

Differences in matrix accumulation and hypertrophy in superficial and deep zone chondrocytes are controlled by bone morphogenetic protein.

Despite the knowledge that superficial zone chondrocytes (SZC, located within 100 mum of the articular surface) and deep zone chondrocytes (DZC, located near the calcified zone) have distinct phenotypes, previous studies on bone morphogenetic proteins (BMPs) have not differentiated its effects on SZC versus DZC. Using a pellet culture model we have compared phenotype, morphology and matrix accumulation in SZC and DZC with or without adenovirus-mediated overexpression of BMP2 or -7 or the BMP antagonist Noggin. Greater accumulation of proteoglycan (PG)-rich matrix in the untreated DZC was associated with a hypertrophic phenotype with large cell diameters and high gene expression levels of runt-related transcription factor-2 (Runx2) as well as higher endogenous BMP activity. Noggin overexpression decreased matrix accumulation and cell diameters in SZC and DZC, confirming a role for endogenous BMP in both processes. In DZC, overexpression of either BMP2 or -7 increased cell diameter without increasing PG-rich matrix accumulation. In contrast, in SZC, BMP overexpression increased matrix accumulation and type II collagen gene expression without increasing cell diameter. These data indicate that differences in endogenous BMP activity level and responsiveness to BMPs define, in part, the differences between the SZC and DZC phenotype. They also suggest that SZC may be a more appropriate target for BMP therapy than DZC.

All-Cause Versus Complication-Specific Readmission Following Total Knee Arthroplasty.

BACKGROUND: Unplanned readmissions have become an important quality indicator, particularly for reimbursement; thus, accurate assessment of readmission frequency and risk factors for readmission is critical. The purpose of this study was to determine (1) the frequency of and (2) risk factors for readmissions for all causes or procedure-specific complications within 30 days after total knee arthroplasty (TKA) as well as (3) the association between hospital volume and readmission rate. METHODS: The Statewide Planning and Research Cooperative System (SPARCS) database from the New York State Department of Health was used to identify 377,705 patients who had undergone primary TKA in the period from 1997 to 2014. Preoperative diagnoses, comorbidities, and postoperative complications were determined using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes. Readmission was defined as all-cause, due to complications considered by the Centers for Medicare & Medicaid Services (CMS) to be TKA-specific, or due to an expanded list of TKA-specific complications based on expert opinion. Multivariable logistic regression analysis was utilized to determine the independent predictors of readmission within 30 days after surgery. RESULTS: There were 22,076 all-cause readmissions-a rate of 5.8%, with a median rate of 3.9% (interquartile range [Q1, Q3] = 1.1%, 7.2%]) among the hospitals-within 30 days after discharge. Of these, only 11% (0.7% of all TKAs) were due to complications considered to be TKA-related by the CMS whereas 31% (1.8% of all TKAs) were due to TKA-specific complications on the expanded list based on expert opinion. Risk factors for TKA-specific readmissions based on the expanded list of criteria included an age of >85 years (odds ratio [OR] = 1.32, 95% confidence interval [CI] = 1.15 to 1.52), male sex (OR = 1.41, 95% CI = 1.34 to 1.49), black race (OR = 1.24, 95% CI = 1.14 to 1.34), Medicaid coverage (OR = 1.40, 95% CI = 1.26 to 1.57), and comorbidities. Several comorbid conditions contributed to the all-cause but not the TKA-specific readmission risk. Very low hospital volume (<90 cases per year) was associated with a higher readmission risk. CONCLUSIONS: The frequency of readmissions for TKA-specific complications was low relative to the frequency of all-cause readmissions. Reasons for hospital readmission are multifactorial and may not be amenable to simple interventions. Health-care-quality measurement of readmission rates should be calculated and risk-adjusted on the basis of procedure-specific criteria. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Noggin regulation of bone morphogenetic protein (BMP) 2/7 heterodimer activity in vitro.

Bone morphogenic proteins (BMPs) are growth factors important for skeletal development and bone growth. Noggin, one of the soluble BMP antagonists, regulates the action of BMPs on mesenchymal precursor cells, partially through a feedback type of inhibition. In this study, we constructed a novel BMP2/7 'fusion gene' that encodes both BMP2 and BMP7 genes in tandem by a linker. Polymerase chain reaction (PCR) and Western blotting showed that the BMP2/7 fusion gene construct led to the production of BMP2/7 heterodimers in A549 'producer' cells. When applied to C2C12 myoblastic cells, BMP2/7 heterodimers increased alkaline phosphatase (ALP) activity and osteocalcin (OCN) expression (markers of osteoblastic differentiation) more effectively than either BMP2 or BMP7 homodimers. Moreover, this heterodimer induced significantly lower levels of Noggin expression in C2C12 cells than respective homodimers at similar doses. The addition of Noggin did not affect the heterodimer's activities in increasing osteoblastic differentiation in C2C12 cells. In contrast, BMP2 and BMP7 homodimers were largely inhibited by Noggin. Our finding suggests that the 'fusion gene' construct led to the production of bioactive BMP2/7 heterodimers, which were not antagonized by Noggin as effectively as it to BMP homodimers. The weaker Noggin antagonism on BMP heterodimers compared to homodimers may contribute to increased osteogenic potency of heterodimers in vitro and in vivo.

Effects of hepatocyte growth factor and platelet-derived growth factor on the repair of meniscal defects in vitro.

Injuries to the avascular region of the meniscus occur frequently and may be difficult to repair. This study was designed to determine whether growth factors could diffuse from a collagen sponge or a collagen gel into meniscal tissue and stimulate healing of defects using an in vitro model. The diffusion of platelet-derived growth factor (PDGF) from the collagen carriers into the medium was rapid with approximately 50% being released from the collagen sponge within the first hour. After 5 d of incubation, 8% of the PDGF was present in the meniscus, 11% in the collagen sponge, and 62% had been released into the medium. Similar results were obtained when a collagen gel was used as a carrier. Histological evaluation of the meniscal explants after 2 wk in culture revealed extensive proteoglycan staining in the areas surrounding defects treated with either hepatocyte growth factor (HGF) or PDGF compared with controls without growth factor. The HGF-PDGF treatment resulted in alignment and migration of meniscal cells toward the defect, which was not observed in untreated controls. At 3-7 d, increased number of cells were observed in defects treated with collagen gels (but not the sponge) with PDGF-HGF. At 4 wk, combined HGF-PDGF treatment resulted in the formation of tissue with birefringence by polarized microscopy, suggestive of organized collagen. The data suggest that use of specific PDGF-HGF may enhance the repair of meniscal injuries.

Biochemical and biomechanical properties of lesion and adjacent articular cartilage after chondral defect repair in an equine model.

BACKGROUND: Chondral defects may lead to degradative changes in the surrounding cartilage, predisposing patients to developing osteoarthritis. PURPOSE: To quantify changes in the biomechanical and biochemical properties of the articular cartilage adjacent to chondral defects after experimental defect repair. STUDY DESIGN: Controlled laboratory study. METHODS: Specimens were harvested from tissue within (lesion), immediately adjacent to, and at a distance from (remote area) a full-thickness cartilage defect 8 months after cartilage repair with genetically modified chondrocytes expressing insulin-like growth factor-I or unmodified, control chondrocytes. Biomechanical properties, including instantaneous Young's and equilibrium aggregate moduli, were determined by confined compression testing. Biochemical properties, such as water and proteoglycan content, were also measured. RESULTS: The instantaneous Young's modulus, equilibrium modulus, and proteoglycan content increased, whereas water content decreased with increasing distance from the repaired lesion. The instantaneous Young's and equilibrium moduli of the adjacent articular cartilage were 80% and 50% that of remote area samples, respectively, whereas water content increased 0.9% and proteoglycan content was decreased by 35%. No significant changes in biomechanical and biochemical properties were found either in the lesion tissue or in adjacent cartilage with genetic modification of the chondrocytes. CONCLUSION: Articular cartilage adjacent to repaired chondral defects showed significant remodeling 8 months after chondral defect repair, regardless of whether genetically modified or unmodified cells were implanted. CLINICAL RELEVANCE: Changes in the biochemical and biomechanical properties of articular cartilage adjacent to repaired chondral defects may represent remodeling as part of an adaptive process or degeneration secondary to an altered distribution of joint forces. Quantification of these changes could provide important parameters for assessing progress after operative chondral defect repair.

Combined bone morphogenetic protein-2 and -7 gene transfer enhances osteoblastic differentiation and spine fusion in a rodent model.

UNLABELLED: To enhance the osteogenic activity of BMP, combination BMP2 and BMP7 gene transfer was performed. This approach led to a significant increase in osteoblastic differentiation of mesenchymal precursors compared with single BMP gene transfer in vitro. When tested in 78 rats, combination gene transfer enhanced mechanically stable spine fusion and bone formation rate versus single BMP gene transfer. INTRODUCTION: Although clinical bone morphogenetic protein (BMP) therapy is effective, required doses are very high. Previous studies have suggested that the co-expression of two different BMP genes can result in the production of heterodimeric BMPs that may be more potent than homodimers. In this study, combined BMP2 and BMP7 gene transfer was performed to test whether this approach improves osteoblastic differentiation and bone formation compared with single BMP gene transfer. MATERIALS AND METHODS: A producer cell (A549) was co-transfected with adenovirus vectors encoding BMP2 (AdBMP2) and BMP7 (AdBMP7) or, as controls, each vector alone, AdNull (with no transgene) or no virus. Supernatants were compared for their ability to stimulate osteoblastic differentiation of C2C12 myoblasts and MC3T3-E1 pre-osteoblasts. In a rat posterolateral spine fusion model, co-administration of AdBMP2 and AdBMP7 was compared with treatment with each vector alone, AdNull or no virus in 78 rats. The spines were assessed 8 weeks after surgery for radiographic and mechanical fusion, bone formation, and mineralization. RESULTS: BMP2 and BMP7 were co-precipitated from supernatants of cells co-transfected with AdBMP2 and AdBMP7, indicating the presence of BMP2/7 heterodimer. Supernatants of co-transfected cells containing relatively low doses (7-140 ng/ml) of BMPs induced osteocalcin expression and alkaline phosphatase activity in both C2C12 and MC3T3-E1 cells, that were up to 6- and 40-fold higher, respectively, than levels induced by maximal doses (200-1000 ng/ml) of either BMP2 or BMP7 alone. In the spine fusion model, co-administration of AdBMP2 and AdBMP7 resulted in a significantly greater number of mechanically stable fusions and also 2-fold higher mineralization rate and bone volume in the fusion mass versus single BMP gene transfer (p < 0.02, all comparisons). CONCLUSION: Combined BMP2 and BMP7 gene transfer is significantly more effective in inducing osteoblastic differentiation and spine fusion than individual BMP gene transfer.