Advances with Platelet-Rich Plasma for Bone Healing.

Despite significant advances in the understanding and delivery of osteosynthesis, fracture non-union remains a challenging clinical problem in orthopaedic surgery. To bridge the gap, basic science characterization of fracture healing provides a platform to identify and target biological strategies to enhance fracture healing. Of immense interest, Platelet-rich plasma (PRP) is a point of care orthobiologic that has been extensively studied in bone and soft tissue healing given its relative ease of translation from the benchtop to the clinic. The aim of this narrative review is to describe and relate pre-clinical in-vitro and in-vivo findings to clinical observations investigating the efficacy of PRP to enhance bone healing for primary fracture management and non-union treatment. A particular emphasis is placed on the heterogeneity of PRP preparation techniques, composition, activation strategies, and delivery. In the context of existing data, the routine use of PRP to enhance primary fracture healing and non-union management cannot be supported. However, it is acknowledged that extensive heterogeneity of PRP treatments in clinical studies adds obscurity; ultimately, refinement (and consensus) of PRP treatments for specific clinical indications, including repetition studies are warranted.

Editorial Commentary: The Statistical Fragility Index of Medical Trials Is Low By Design: Critical Evaluation of Confidence Intervals Is Required.

The Fragility Index (FI) provides the number of patients whose outcome would need to have changed for the results of a clinical trial to no longer be statistically significant. Although it's a well-intended and easily interpreted metric, its calculation is based on reversing a significant finding and therefore its interpretation is only relevant in the domain of statistical significance. Its interpretation is only relevant in the domain of statistical significance. A well-designed clinical trial includes an a priori sample size calculation that aims to find the bare minimum of patients needed to obtain statistical significance. Such trials are fragile by design! Examining the robustness of clinical trials requires an estimation of uncertainty, rather than a misconstrued, dichotomous focus on statistical significance. Confidence intervals (CIs) provide a range of values that are compatible with a study's data and help determine the precision of results and the compatibility of the data with different hypotheses. The width of the CI speaks to the precision of the results, and the extent to which the values contained within have potential to be clinically important. Finally, one should not assume that a large FI indicates robust findings. Poorly executed trials are prone to bias, leading to large effects, and therefore, small P values, and a large FI. Let's move our future focus from the FI toward the CI.

How accurate are positive preoperative aspiration culture results in shoulder periprosthetic joint infection? A concordance study.

BACKGROUND: The concordance between preoperative synovial fluid cultures and intraoperative tissue cultures for identifying pathogenic microorganisms in shoulder periprosthetic joint infection (PJI) remains poorly understood. The purpose of our study was to examine the diagnostic accuracy of positive synovial fluid culture results in early pathogen identification for shoulder PJI. METHODS: A total of 35 patients who met the Musculoskeletal Infection Society criteria for PJI following primary anatomic or reverse arthroplasty and the study inclusion criteria were identified retrospectively from a single institution (multiple surgeons) from January 2011 to June 2021. The inclusion criteria required a positive preoperative intra-articular synovial fluid sample within 90 days analyzed within the same institution and intraoperative tissue cultures at the time of arthrotomy. Concordance was determined when the organism(s) identified from the aspirate correlated with the intraoperative specimens. RESULTS: Overall concordance was identified in 28 of 35 patients (80%), with similar concordance for anatomic (21 of 24, 88%) and reverse (7 of 11, 64%) shoulder arthroplasties (P = .171). Culture discordance occurred in 7 of 35 patients (20%): of these, 5 (14%) had no corresponding intraoperative culture growth whereas 2 (6%) had polymicrobial intraoperative cultures. Monomicrobial Cutibacterium acnes PJI cases were the most common (24 of 35, 69%) and had an overall concordance rate of 79%. Of 5 discordant C acnes patients, 2 had polymicrobial intraoperative cultures and 3 had negative intraoperative culture results; all the patients with negative intraoperative culture results had received antibiotics between the time of aspiration and surgery. Considered separately, concordance in patients who had a positive aspirate finding for C acnes and did not receive antibiotics prior to surgery was 19 of 21 (90%), with a sensitivity of 100% (95% confidence interval, 82%-100%) and a corresponding positive predictive value of 0.91 (95% confidence interval, 58%-93%). CONCLUSION: Preoperative positive aspiration culture results demonstrated favorable sensitivity and specificity when compared with intraoperative tissue cultures in identifying pathogenic microorganisms in shoulder PJI patients. These findings are congruent with literature from hip and knee arthroplasty. Ultimately, confidence in the accuracy of positive preoperative aspiration culture results in shoulder PJI may facilitate the development of early, targeted treatment strategies while directing patient expectations and risk.

Design and Preclinical Evaluation of a Novel B7-H4-Directed Antibody-Drug Conjugate, AZD8205, Alone and in Combination with the PARP1-Selective Inhibitor AZD5305.

PURPOSE: We evaluated the activity of AZD8205, a B7-H4-directed antibody-drug conjugate (ADC) bearing a novel topoisomerase I inhibitor (TOP1i) payload, alone and in combination with the PARP1-selective inhibitor AZD5305, in preclinical models. EXPERIMENTAL DESIGN: IHC and deep-learning-based image analysis algorithms were used to assess prevalence and intratumoral heterogeneity of B7-H4 expression in human tumors. Several TOP1i-ADCs, prepared with Val-Ala or Gly-Gly-Phe-Gly peptide linkers, with or without a PEG8 spacer, were compared in biophysical, in vivo efficacy, and rat toxicology studies. AZD8205 mechanism of action and efficacy studies were conducted in human cancer cell line and patient-derived xenograft (PDX) models. RESULTS: Evaluation of IHC-staining density on a per-cell basis revealed a range of heterogeneous B7-H4 expression across patient tumors. This informed selection of bystander-capable Val-Ala-PEG8-TOP1i payload AZ14170133 and development of AZD8205, which demonstrated improved stability, efficacy, and safety compared with other linker-payload ADCs. In a study of 26 PDX tumors, single administration of 3.5 mg/kg AZD8205 provided a 69% overall response rate, according to modified RECIST criteria, which correlated with homologous recombination repair (HRR) deficiency (HRD) and elevated levels of B7-H4 in HRR-proficient models. Addition of AZD5305 sensitized very low B7-H4-expressing tumors to AZD8205 treatment, independent of HRD status and in models representing clinically relevant mechanisms of PARPi resistance. CONCLUSIONS: These data provide evidence for the potential utility of AZD8205 for treatment of B7-H4-expressing tumors and support the rationale for an ongoing phase 1 clinical study (NCT05123482). See related commentary by Pommier and Thomas, p. 991.

Efficacy, Tolerability, and Pharmacokinetic Studies of Antibody-Drug Conjugates Containing a Low-Potency Pyrrolobenzodiazepine Dimer.

Antibody-drug conjugate (ADC) research has typically focused on the release of highly potent cytotoxic agents to achieve antitumor efficacy. However, recently approved ADCs trastuzumab deruxtecan and sacituzumab govitecan release lower-potency topoisomerase inhibitors. This has prompted interest in ADCs that release lower-potency cytotoxic drugs to potentially enhance therapeutic index and reduce unwanted toxicity. Pyrrolobenzodiazepine (PBD) dimer ADCs have been widely investigated in human clinical trials, which have focused on high-potency PBDs. In this study, we evaluated five ADCs that release the low-potency PBD dimer SG3650. The relatively low clogD for this agent facilitated higher drug-to-antibody ratio (DAR) conjugation without the need for antibody engineering or functionalization of the drug. The rank order of potency for DAR 2 site-specific ADCs (conjugated at the C239i position) matched the order for the corresponding free drugs in vitro. Despite free drug SG3650 being inactive in vivo, the DAR 2 ADCs derived from the corresponding drug-linker SG3584 showed antitumor efficacy in solid (anti-HER2) and hematologic (anti-CD22) xenograft models. Antitumor activity could be enhanced by conjugating SG3584 to trastuzumab at higher DARs of 4 and 8 and by adjusting dosing and schedule. Higher-DAR conjugates were stable and displayed good rat pharmacokinetic profiles as measured by ELISA and LC/MS-MS. A single intravenous dose of isotype control SG3584 DAR 2 ADC resulted in no mortality in rats or monkeys at doses of up to 25 and 30 mg/kg, respectively. These findings suggest that further investigations of low-potency PBD dimers in ADCs that target hematologic and solid tumors are warranted.

Surgical approach to pediatric mediastinal masses based on imaging characteristics.

BACKGROUND: Pediatric mediastinal masses may be resected using an open or video-assisted thoracoscopic surgery (VATS) approach. We sought to define the preoperative imaging findings predicting amenability to VATS. METHODS: This multicenter retrospective study of pediatric patients undergoing either VATS or open surgical mediastinal mass resection between 2008 and 2018 evaluated the preoperative imaging descriptors associated with VATS. Postoperative endpoints included length of stay (LOS), 30-day readmission, 90-day mortality and complication rates. RESULTS: Mediastinal mass resection was performed in 33 patients. Median tumor size was 6 cm, and 51.5% had anterior mediastinal tumors. The 23 (69.7%) patients who underwent VATS were significantly older (144 months vs 32, P = 0.01) and larger (33.6 kg vs 13.8 P = 0.03). Preoperative imaging characteristics in VATS included "well circumscribed", "smooth margins" and "cystic", while the open surgery group were "heterogeneous" and "coarse calcification". The open group had more germ cell tumors (60.0% vs 13.0%, P = 0.16) but no difference in malignancy. VATS patients had shorter LOS (2 days vs 6.5, P = 0.24). Readmission, complication and mortality rates were similar. CONCLUSIONS: Pediatric patients with apparent malignancy frequently underwent open resection compared with the thoracoscopic group, although final malignant pathology was similar. Equivalent outcomes and shorter LOS should favor a minimally invasive approach. LEVEL OF EVIDENCE: Level III.

Fe-Rich Fossil Vents as Mars Analog Samples: Identification of Extinct Chimneys in Miocene Marine Sediments Using Raman Spectroscopy, X-Ray Diffraction, and Scanning Electron Microscopy-Energy Dispersive X-Ray Spectroscopy.

On Earth, the circulation of Fe-rich fluids in hydrothermal environments leads to characteristic iron mineral deposits, reflecting the pH and redox chemical conditions of the hydrothermal system, and is often associated with chemotroph microorganisms capable of deriving energy from chemical gradients. On Mars, iron-rich hydrothermal sites are considered to be potentially important astrobiological targets for searching evidence of life during exploration missions, such as the Mars 2020 and the ExoMars 2022 missions. In this study, an extinct hydrothermal chimney from the Jaroso hydrothermal system (SE Spain), considered an interesting geodynamic and mineralogical terrestrial analog for Mars, was analyzed using Raman spectroscopy, X-ray diffraction, and scanning electron microscopy coupled with energy dispersive X-ray spectroscopy. The sample consists of a fossil vent in a Miocene shallow-marine sedimentary deposit composed of a marl substrate, an iron-rich chimney pipe, and a central space filled with backfilling deposits and vent condensates. The iron crust is particularly striking due to the combined presence of molecular and morphological indications of a microbial colonization, including mineral microstructures (e.g., stalks, filaments), iron oxyhydroxide phases (altered goethite, ferrihydrite), and organic signatures (carotenoids, organopolymers). The clear identification of pigments by resonance Raman spectroscopy and the preservation of organics in association with iron oxyhydroxides by Raman microimaging demonstrate that the iron crust was indeed colonized by microbial communities. These analyses confirm that Raman spectroscopy is a powerful tool for documenting the habitability of such historical hydrothermal environments. Finally, based on the results obtained, we propose that the ancient iron-rich hydrothermal pipes should be recognized as singular terrestrial Mars analog specimens to support the preparatory work for robotic in situ exploration missions to Mars, as well as during the subsequent interpretation of data returned by those missions.

Is Metformin Use Associated with Prolonged Overall Survival in Patients with Soft Tissue Sarcoma? A SEER-Medicare Study.

BACKGROUND: Metformin, an oral drug used to treat patients with diabetes, has been associated with prolonged survival in patients with various visceral carcinomas. Although the exact mechanisms are unknown, preclinical translational studies demonstrate that metformin may impair tumor cellular metabolism, alter matrix turnover, and suppress oncogenic signaling pathways. Currently used chemotherapeutic agents have not been very successful in the adjuvant setting or for treating patients with metastatic sarcomas. We wanted to know whether metformin might be associated with improved survival in patients with a soft tissue sarcoma. QUESTIONS/PURPOSES: In patients treated for a soft tissue sarcoma, we asked: (1) Is there an association between metformin use and longer survival? (2) How does this association differ, if at all, among patients with and without the diagnosis of diabetes? METHODS: The Surveillance, Epidemiology, and End Results-Medicare (SEER-Medicare) database was used to identify patients with a diagnosis of soft tissue sarcoma from 2007 to 2016. Concomitant medication use was identified using National Drug Codes using the Medicare Part D event files. This database was chosen because of the large number of captured sarcoma patients, availability of tumor characteristics, and longitudinal linkage of Medicare data. A total of 14,650 patients were screened for inclusion. Patients with multiple malignancies, diagnosis at autopsy, or discrepant linkage to the Medicare database were excluded. Overall, 4606 patients were eligible for the study: 598 patients taking metformin and 4008 patients not taking metformin. A hazard of mortality (hazard ratio) was analyzed comparing patients taking metformin with those patient groups not taking metformin and expressed in terms of a 95% confidence interval. Cox regression analysis was used to control for patient-specific, disease-specific, and treatment-specific covariates. RESULTS: Having adjusted for disease-, treatment-, and patient-specific characteristics, patients taking metformin experienced prolonged survival compared with all patients not taking metformin (HR 0.76 [95% CI 0.66 to 0.87]). Associated prolonged survival was also seen when patients taking metformin were compared with those patients not on metformin irrespective of a diabetes diagnosis (HR 0.79 [95% CI 0.66 to 0.94] compared with patients with a diagnosis of diabetes and HR 0.77 [95% CI 0.67 to 0.89] compared with patients who did not have a diagnosis of diabetes). CONCLUSION: Without suggesting causation, we found that even after controlling for confounding variables such as Charlson comorbidity index, tumor grade, size, stage, and surgical/radiation treatment modalities, there was an association between metformin use and increased survival in patients with soft tissue sarcoma. When considered separately, this association persisted in patients not on metformin with and without a diabetes diagnosis. Although metformin is not normally prescribed to patients who do not have a diabetes diagnosis, these data support further study, and if these findings are substantiated, it might lead to the performance of multicenter, prospective clinical trials about the use of metformin as an adjuvant therapy for the treatment of soft tissue sarcoma in patients with and without a preexisting diabetes diagnosis. LEVEL OF EVIDENCE: Level III, therapeutic study.

Effect of Vancomycin Soaking on Anterior Cruciate Ligament Graft Biomechanics.

PURPOSE: To evaluate the effect of soaking of anterior cruciate ligament (ACL) grafts in vancomycin solution on graft biomechanical properties at the time of implantation. METHODS: The central third of patellar tendons was harvested from mature bovine knees and prepared as a tendon-only graft or a bone-tendon-bone (BTB) graft. Tendons were wrapped in gauze soaked in vancomycin solution (VS) (5 mg/mL) or normal saline (NS) and left to stand for 30 minutes at room temperature, simulating graft exposure times in the operating room during ACL reconstruction. Tensile testing was carried out on a materials testing system with (1) low-magnitude loading (60 N at 3 mm/s) with repeated testing of tendon-only grafts; and (2) high-magnitude loading (600 N at 10 mm/min) of BTB grafts. For tendon-only grafts, specimens were first wrapped in NS-soaked gauze and underwent testing, with repeated testing performed after wrapping in gauze soaked in VS or buffered VS (pH 7.0). For BTB grafts, specimens were randomly assigned to treatment with VS or NS. RESULTS: For tendon-only grafts, there was no difference in Young's modulus (YM) after soaking with VS soaking (baseline, 12.69 MPa; treatment, 16.07 ± 4.44 MPa; P = .99) or buffered VS (baseline, 12.45 ± 4.55 MPa; treatment, 15.56 ± 2.83 MPa; P = .99). For BTB grafts, there were no differences in elongation strain (VS, 46.8% ± 7.0%; NS, 31.5% ± 13.5%, P = .19) or YM (VS, 158.4 ± 15.8 MPa; NS, 158.5 ± 23.3 MPa, P = .99). CONCLUSIONS: According to controlled biomechanical tests, vancomycin soaking of patellar tendon grafts does not adversely affect time-zero material properties. CLINICAL RELEVANCE: This study suggests that vancomycin wrapping has no immediate adverse effects on the biomechanical properties of ACL grafts. Randomized controlled trials are warranted to validate the widespread use of vancomycin soaking of tendon grafts for infection prophylaxis during ACL reconstruction.

Growth Factor Delivery to a Cartilage-Cartilage Interface Using Platelet-Rich Concentrates on a Hyaluronic Acid Scaffold.

PURPOSE: To determine whether (1) human leukocyte-platelet-rich plasma (L-PRP) or (2) leukocyte-platelet-rich fibrin (L-PRF) delivered on a hyaluronic acid (HA) scaffold at a bovine chondral defect, a simulated cartilage tear interface, in vitro would improve tissue formation based on biomechanical, histologic, and biochemical measures. METHODS: L-PRF and L-PRP were prepared from 3 healthy volunteer donors and delivered in conjunction with HA scaffolds to defects created in full-thickness bovine cartilage plugs harvested from bovine femoral condyle and trochlea. Specimens were cultured in vitro for up to 42 days. Treatment groups included an HA scaffold alone and scaffolds containing L-PRF or L-PRP. Cartilage repair was assessed using biomechanical testing, histology, DNA quantification, and measurement of sulfated glycosaminoglycan and collagen content at 28 and 42 days. RESULTS: L-PRF elicited the greatest degree of defect filling and improvement in other histologic measures. L-PRF-treated specimens also had the greatest cellularity when compared with L-PRP and control at day 28 (560.4 µg vs 191.4 µg vs 124.2 µg, P = .15); at day 48, there remained a difference, although not significant, between L-PRF versus L-PRP (761.1 µg vs 589.3 µg, P = .219) . L-PRF had greater collagen deposition when compared with L-PRP at day 42 (40.1 µg vs 16.3 µg, P < .0001). L-PRF had significantly greater maximum interfacial strength compared with the control at day 42 (10.92 N vs 0.66 N, P = .015) but had no significant difference compared with L-PRP (10.92 N vs 6.58 N, P = .536). L-PRP facilitated a greater amount of sulfated glycosaminoglycan production at day 42 when compared with L-PRF (15.9 µg vs 4.3 µg, P = .009). CONCLUSIONS: Delivery of leukocyte-rich platelet concentrates in conjunction with a HA scaffold may allow for improvements in cartilage healing through different pathways. L-PRF was not superior to L-PRP in its biomechanical strength, suggesting that both treatments may be effective in improving biomechanical strength of healing cartilage through different pathways. CLINICAL RELEVANCE: The delivery of platelet-rich concentrates in conjunction HA scaffolds may augment healing cartilaginous injuries.

Investigating the Osteoinductive Potential of a Decellularized Xenograft Bone Substitute.

Bone grafting is the second most common tissue transplantation procedure worldwide. One of the alternative methods for bone repair under investigation is a tissue-engineered bone substitute. An ideal property of tissue-engineered bone substitutes is osteoinductivity, defined as the ability to stimulate primitive cells to differentiate into a bone-forming lineage. In the current study, we use a decellularization and oxidation protocol to produce a porcine bone scaffold and examine whether it possesses osteoinductive potential and can be used to create a tissue-engineered bone microenvironment. The decellularization protocol was patented by our lab and consists of chemical decellularization and oxidation steps using combinations of deionized water, trypsin, antimicrobials, peracetic acid, and triton-X100. To test if the bone scaffold was a viable host, preosteoblasts were seeded and analyzed for markers of osteogenic differentiation. The osteoinductive potential was observed in vitro with similar osteogenic markers being expressed in preosteoblasts seeded on the scaffolds and demineralized bone matrix. To assess these properties in vivo, scaffolds with and without preosteoblasts preseeded were subcutaneously implanted in mice for 4 weeks. MicroCT scanning revealed 1.6-fold increased bone volume to total volume ratio and 1.4-fold increase in trabecular thickness in scaffolds after implantation. The histological analysis demonstrates new bone formation and blood vessel formation with pentachrome staining demonstrating osteogenesis and angiogenesis, respectively, within the scaffold. Furthermore, CD31+ staining confirmed the endothelial lining of the blood vessels. These results demonstrate that porcine bone maintains its osteoinductive properties after the application of a patented decellularization and oxidation protocol developed in our laboratory. Future work must be performed to definitively prove osteogenesis of human mesenchymal stem cells, biocompatibility in large animal models, and osteoinduction/osseointegration in a relevant clinical model in vivo. The ability to create a functional bone microenvironment using decellularized xenografts will impact regenerative medicine, orthopedic reconstruction, and could be used in the research of multiple diseases.

Surgical management of type II superior labrum anterior posterior (SLAP) lesions: a review of outcomes and prognostic indicators.

A Type II SLAP (superior labrum anterior posterior) lesion is a tear of the superior glenoid labrum with involvement of the long head of the biceps tendon insertion. In patients that do not improve with conservative treatment, there is a great deal of variability in the surgical management of these injuries that includes arthroscopic SLAP repair, arthroscopic SLAP repair with biceps tenodesis, biceps tenodesis alone and biceps tenotomy. Each surgical technique has specific effects on a patient's postoperative course and functional recovery. Rehabilitation strategies may be best formulated on an individual basis with an open line of communication between the operating surgeon and the physical therapist. Despite an increased incidence in treatment, there is currently no consensus on the optimal surgical procedure or treatment algorithm for Type II SLAP injuries. However, in middle-aged or older patients (>35) with Type II SLAP tears, either arthroscopic suprapectoral or mini-open subpectoral biceps tenodesis is recommended due to the higher failure rates observed with arthroscopic SLAP repair in this patient group. Although more patients present with a 'Popeye' sign after biceps tenotomy, long-term functional outcome is similar between biceps tenodesis compared to tenotomy. However, more patients will experience biceps fatigue or cramping after the tenotomy procedure. Biceps tenodesis is preferred in younger, more active patients, while tenotomy is preferred in the middle-aged or older and lower demand patients. The aim of this paper is to provide a brief description of the different surgical techniques employed to address Type II SLAP lesions (arthroscopic repair, biceps tenodesis, and biceps tenotomy) and provide a review of available literature regarding outcomes and prognostic factors associated with each technique.

The etiology, evaluation, and management of plantar fibromatosis.

Plantar fibromatosis (Ledderhose disease) is a rare, benign, hyperproliferative fibrous tissue disorder resulting in the formation of nodules along the plantar fascia. This condition can be locally aggressive, and often results in pain, functional disability, and decreased quality of life. Diagnosis is primarily clinical, but MRI and ultrasound are useful confirmatory adjuncts. Given the benign nature of this condition, treatment has historically involved symptomatic management. A multitude of conservative treatment strategies supported by varying levels of evidence have been described mostly in small-scale trials. These therapies include steroid injections, verapamil, radiation therapy, extracorporeal shock wave therapy, tamoxifen, and collagenase. When conservative measures fail, surgical removal of fibromas and adjacent plantar fascia is often done, although recurrence is common. This review aims to provide a broad overview of the clinical features of this disease as well as the current treatment strategies being employed in the management of this condition.

The Subchondral Bone Is Affected by Bone Marrow Stimulation: A Systematic Review of Preclinical Animal Studies.

OBJECTIVE: Despite the mechanical and biological roles of subchondral bone (SCB) in articular cartilage health, there remains no consensus on the postoperative morphological status of SCB following bone marrow stimulation (BMS). The purpose of this systematic review was to clarify the morphology of SCB following BMS in preclinical, translational animal models. DESIGN: The MEDLINE and EMBASE databases were systematically reviewed using specific search terms on April 19, 2016 based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The morphology of the SCB was assessed using of microcomputed tomography (bone density) and histology (microscopic architecture). RESULTS: Seventeen animal studies with 520 chondral lesions were included. The morphology of SCB did not recover following BMS. Compared with untreated chondral defects, BMS resulted in superior morphology of superficial SCB and cartilage but inferior morphology (specifically bone density, P < 0.05) of the deep SCB. Overall, the use of biological adjuvants during BMS resulted in the superior postoperative morphology of SCB. CONCLUSIONS: Alterations in the SCB following BMS were confirmed. Biologics adjuvants may improve the postoperative morphology of both SCB and articular cartilage. Refinements of BMS techniques should incorporate consideration of SCB damage and restoration. Investigations to optimize BMS techniques incorporating both minimally invasive approaches and biologically augmented platforms are further warranted.

Comparison of Bone Tunnel and Cortical Surface Tendon-to-Bone Healing in a Rabbit Model of Biceps Tenodesis.

BACKGROUND: Many orthopaedic surgical procedures involve reattachment of a single tendon to bone. Whether tendon-to-bone healing is better facilitated by tendon fixation within a bone tunnel or on a cortical surface is unknown. The purpose of this study was to evaluate tendon-healing within a bone tunnel compared with that on the cortical surface in a rabbit model of biceps tenodesis. METHODS: Thirty-two rabbits (24 weeks of age) underwent unilateral proximal biceps tenodesis with tendon fixation within a bone tunnel (BT group) or on the cortical surface (SA [surface attachment] group). Postoperatively, rabbits were allowed free-cage activity without immobilization. All rabbits were killed 8 weeks after surgery. Healing was assessed by biomechanical testing, microcomputed tomography (micro-CT), and histomorphometric analysis. RESULTS: Biomechanical testing demonstrated no significant difference between the groups in mean failure loads (BT: 56.8 ± 28.8 N, SA: 55.8 ± 14.9 N; p = 0.92) or stiffness (BT: 26.3 ± 16.6 N/mm, SA: 32.3 ± 9.6 N/mm; p = 0.34). Micro-CT analysis demonstrated no significant difference between the groups in mean volume of newly formed bone (BT: 69.3 ± 13.9 mm, SA: 65.5 ± 21.9 mm; p = 0.70) or tissue mineral density of newly formed bone (BT: 721.4 ± 10.9 mg/cm, SA: 698.6 ± 26.2 mg/cm; p = 0.07). On average, newly formed bone within the tunnel represented only 5% of the total new bone formed in the BT specimens. Histological analysis demonstrated tendon-bone interdigitation and early fibrocartilaginous zone formation on the outer cortical surface in both groups. In contrast, minimal tendon-bone bonding was observed within the tunnel in the BT specimens. CONCLUSIONS: Tendon fixation in a bone tunnel and on the cortical surface resulted in similar healing profiles. For tendons placed within a bone tunnel, intratunnel healing was minimal compared with the healing outside the tunnel on the cortical surface. CLINICAL RELEVANCE: The creation of large bone tunnels, which can lead to stress risers and increase the risk of fracture, may not be necessary for biceps tenodesis procedures.

Biomechanics and Microstructural Analysis of the Mouse Knee and Ligaments.

The purpose of this study is to determine the feasibility of using murine models for translational study of knee ligament injury, repair, and reconstruction. To achieve this aim, we provide objective, quantitative data detailing the gross anatomy, biomechanical characteristics, and microscopic structure of knee ligaments of 44 male mice (C57BL6, 12 weeks of age). Biomechanical testing determined the load-to-failure force, stiffness, and the site of ligament failure for the anterior cruciate ligament (ACL), posterior cruciate ligament (PCL), and the medial and lateral collateral ligaments (MCL and LCL). These data are complemented by histological characterization of each of the knee ligaments. In addition, the osseous morphology of the mouse knee was examined using high-resolution nanofocus computed tomography (CT), while standard micro-CT was employed to measure bone morphometrics of the distal femur and proximal tibia. Collectively, our findings suggest that the gross anatomy of the mouse knee is similar to the human knee despite some minor differences and features unique to the murine knee. The ACL had the highest load to failure (5.60 ± 0.75 N), the MCL (3.33 ± 1.45 N), and the PCL (3.45 ± 0.84 N) were similar, and the LCL (1.44 ± 0.37 N) had the lowest load to failure and stiffness. Murine models provide a unique opportunity to focus on biological processes that impact ligament pathology and healing due to the availability of transgenic strains. Our data support their use as a translational platform for the in vivo study of ligament injury, repair, and reconstruction.

Straightforward Glycoengineering Approach to Site-Specific Antibody-Pyrrolobenzodiazepine Conjugates.

Antibody-drug conjugates (ADCs) have become a powerful platform to deliver cytotoxic agents selectively to cancer cells. ADCs have traditionally been prepared by stochastic conjugation of a cytotoxic drug using an antibody's native cysteine or lysine residues. Through strategic selection of the mammalian expression host, we were able to introduce azide-functionalized glycans onto a homogeneously glycosylated anti-EphA2 monoclonal antibody in one step. Conjugation with an alkyne-bearing pyrrolobenzodiazepine dimer payload (SG3364) using copper-catalyzed click chemistry yielded a site-specific ADC with a drug-to-antibody ratio (DAR) of four. This ADC was compared with a glycoengineered DAR two site-specific ADC, and both were found to be highly potent against EphA2-positive human prostate cancer cells in both an in vitro cytotoxicity assay and a murine tumor xenograft model.

Biomechanical Basis of Shoulder Osseous Deformity and Contracture in a Rat Model of Brachial Plexus Birth Palsy.

BACKGROUND: The purpose of this study was to investigate the relative contributions of two proposed mechanisms, strength imbalance and impaired longitudinal muscle growth, to osseous and postural deformity in a rat model of brachial plexus birth palsy (BPBP). METHODS: Thirty-two Sprague-Dawley rat pups were divided into four groups on the basis of surgical interventions to induce a strength imbalance, impaired growth, both a strength imbalance and impaired growth (a combined mechanism), and a sham condition in the left forelimb. Maximum passive external shoulder rotation angle (ERmax) was measured bilaterally at four and eight weeks postoperatively. After the rats were killed at eight weeks, the glenohumeral geometry (on microcomputed tomography) and shoulder muscle architecture properties were measured bilaterally. RESULTS: Bilateral muscle mass and optimal length differences were greatest in the impaired growth and combined mechanism groups, which also exhibited >15° lower ERmax (p < 0.05; four weeks postoperatively), 14° to 18° more glenoid declination (p < 0.10), and 0.76 to 0.94 mm more inferior humeral head translation (p < 0.10) on the affected side. Across all four groups, optimal muscle length was significantly correlated with at least one osseous deformity measure for six of fourteen muscle compartments crossing the shoulder on the affected side (p < 0.05). In the strength imbalance group, the glenoid was 5° more inclined and the humeral head was translated 7.5% more posteriorly on the affected side (p < 0.05). CONCLUSIONS: Impaired longitudinal muscle growth and shoulder deformity were most pronounced in the impaired growth and combined mechanism groups, which underwent neurectomy. Strength imbalance was associated with osseous deformity to a lesser extent. CLINICAL RELEVANCE: Treatments to alleviate shoulder deformity should address mechanical effects of both strength imbalance and impaired longitudinal muscle growth, with an emphasis on developing new treatments to promote growth in muscles affected by BPBP.

Can platelet-rich plasma enhance anterior cruciate ligament and meniscal repair?

The use of platelet-rich plasma (PRP) to improve clinical outcome following a soft tissue injury, regeneration, and repair has been the subject of intense investigation and discussion. This article endeavors to relate clinical and basic science strategies focused on biological augmentation of the healing response in anterior cruciate ligament (ACL) and meniscus repair and replacement using PRP. Therein, a translational feedback loop is created in the literature and targeted towards the entire multidisciplinary team. Ultimately, it is hoped that the theoretical benefits of PRP on soft-tissue interfacial healing will emerge clinically following a careful, focused characterization at the benchtop, and prospective randomized controlled clinical study.

Comparison of transposition techniques to reduce gap associated with high ulnar nerve lesions.

PURPOSE: To determine in a cadaveric model which of 3 anterior transposition techniques allows for maximum gap reduction for high ulnar nerve lesions. METHODS: Six fresh-frozen human adult upper extremity cadaveric transhumeral specimens were used. We anchored the ulnar nerve to bone 10 cm proximal and distal to the medial epicondyle along its exact course while keeping the elbow in 30° flexion as the baseline measurement. We then used a thick suture to mimic and measure the exact course of the nerve between the pins in varying elbow positions. The nerve was then transposed first subcutaneously, then intramuscularly, and then submuscularly while taking exact measurements of the distance the nerve had to travel in varying degrees of elbow flexion for each transposition method. We performed comparative analysis to analyze gap reduction with respect to transposition method and elbow position. RESULTS: Transposing the ulnar nerve reduced the repair gap required to cross the elbow regardless of transposition technique. When comparing individual techniques, however, the greatest gap reduction was achieved by intramuscular, followed by submuscular and finally subcutaneous transposition. A maximum gap reduction of 25 mm (average, 23 mm) was achieved using intramuscular transposition with the elbow in 90° flexion. Subcutaneous transposition actually increased the repair gap when the elbow was in an extended position. CONCLUSIONS: An intramuscular transposition with the elbow in 90° flexion provided the best gap reduction. However, post-neurorrhaphy mobilization may compromise repair site integrity and vascularity if elbow flexion is required to achieve a primary repair, and these factors should be considered carefully when planning treatment. CLINICAL RELEVANCE: This study provides guidance on techniques to reduce nerve gap for primary repair of the ulnar nerve at the elbow using transposition and elbow flexion.