BACKGROUND:Bone marrow stimulation (BMS) is used to treat intra-articular defects, such as articular cartilage defects or to facilitate healing of soft tissue repair; however, BMS yields inconsistent clinical outcomes, potentially due to the inefficient delivery of endogenous progenitor cells. HYPOTHESIS:Combining BMS with localized placement of platelet-derived growth factor (PDGF) would enhance in situ progenitor cell responses, leading to enhanced labral tissue repair and functional recovery in a rat model. STUDY DESIGN:Controlled laboratory study. METHOD:A Bankart glenoid labral tear was created in the right shoulder of 50 adult rats. The animals were randomly divided into 5 groups: (1) healthy (baseline), (2) suture only (control), (3) suture + PDGF, (4) suture + BMS, and (5) suture + PDGF + BMS. Healing was assessed at 1.5 (n = 3), 3, and 8 weeks (n = 4). Baseline groups were included at 3 (n = 4) and 8 weeks (n = 5). At each timepoint, labral healing was evaluated by quantifying progenitor cell recruitment, tissue differentiation, and general morphology. Functional recovery was assessed weekly via gait analysis. RESULTS:BMS alone failed to elicit cell recruitment to the injured labral region. However, the combined BMS + PDGF treatment resulted in a 7-fold increase in progenitor cell accumulation at the tear site compared with BMS alone (27.46 ± 11.51 vs 3.5 ± 3.26 cells/0.01 mm2, respectively; P < .001). The combined group was characterized by increased chondrogenic differentiation, greater glycosaminoglycan intensity, and significantly lower Pauli score. Furthermore, gait analyses confirmed that the combined treatment yielded the most robust functional recovery. CONCLUSION:The synergistic application of BMS + PDGF provided a highly effective method for labral repair compared with isolated treatments, significantly enhancing progenitor cell recruitment, tissue regeneration, and functional recovery. CLINICAL RELEVANCE:This study identifies a novel repair technique that overcomes limitations of standard suture-only repair. This strategy offers a promising translational approach to improve outcomes in shoulder labral reconstruction.

Fracture-related infections are a significant burden to the patient, associated with high health care costs and use of resources. Therefore, prevention is more critical than treatment of infection. There are injury- and patient-related risk factors that are mostly not modifiable, with the exception of a few patient-specific ones such as control of blood glucose levels in patients with diabetes. Measures of prevention can be implemented preoperatively, intraoperatively, and postoperatively.

BACKGROUND:Injuries to the glenoid labrum have been recognized as a source of joint pain and discomfort, which may be associated with the inflammatory responses that lead to the deterioration of labral tissue. However, it is unclear whether the torn labrum prompts mast cell (MC) activation, resulting in synovial inflammatory responses that lead to labral tissue degeneration. PURPOSE:To determine the potential influence of activated MC on synovial inflammatory responses and subsequent labral tissue degeneration and shoulder function deterioration in a rat model by monitoring MC behavior and sequential inflammatory responses within the synovial tissue and labral tissue after injury, suture repair, and MC stabilizer administration. STUDY DESIGN:Controlled laboratory study. METHODS:Anteroinferior glenoid labral tears were generated in the right shoulder of rats (n = 20) and repaired using a tunneled suture technique. Synovial tissue inflammatory responses were modulated in some rats with intraperitoneal administration of an MC stabilizer-cromolyn (n = 10). At weeks 1 and 3, MC activation, synovial inflammatory responses, and labral degeneration were histologically evaluated. Simultaneously, gait analysis was performed before and after surgical repair to assess the worsening of the shoulder function after the injury and treatment. RESULTS:Resident MC degranulation after labral injury (50.48% ± 8.23% activated at week 1) contributed to the initiation of synovial tissue inflammatory cell recruitment, inflammatory product release, matrix metalloproteinase-13, and subsequent labral tissue extracellular matrix degeneration. The administration of cromolyn, an MC stabilizer, was found to significantly diminish injury-mediated inflammatory responses (inflammatory cell infiltration and subsequent proinflammatory product secretion) and improve shoulder functional recovery. CONCLUSION:MC activation is responsible for labral tear-associated synovial inflammation and labral degeneration. The administration of cromolyn can significantly diminish the cascade of inflammatory reactions after labral injury. CLINICAL RELEVANCE:Our findings support the concept that MC stabilizers may be used as a complementary therapeutic option in the treatment and repair of labral tears.

BACKGROUND:The healing capacity of the human glenoid labrum varies by tear location. Current evidence suggests that the healing capacity of meniscal and cartilage injuries relates to cellular composition and vascularity. However, little is known about the histological characteristics of the glenoid labrum and how they may affect healing potential in specific anatomic regions. HYPOTHESIS:Regenerative characteristics of the glenoid labrum differ based on the anatomic region. STUDY DESIGN:Descriptive laboratory study. METHODS:Human glenoid labra from fresh unpreserved cadavers were transversely sectioned in different anatomic regions. Masson trichrome stain was used to determine dense and loose extracellular matrix regions and vessel densities. Hematoxylin and eosin, Ki-67+, and CD90+/CD105+ stains were performed to determine total, proliferative, and progenitor cell densities, respectively. Regression models demonstrated relationships between vascular area, progenitor cell quantity, and probability of successful operation. RESULTS:Among all labral aspects, the superior glenoid labrum had the highest percentage (56.8% ± 6.9%) of dense extracellular matrix or avascular tissue (P < .1). The vascular region of the superior labrum had the fewest total cells (321 ± 135 cells/mm2; P < .01) and progenitor cells (20 ± 4 cells/mm2; P < .001). Vascular area was directly correlated with progenitor cell quantity (P = .006002). An increase in probability of successful operation was associated with a linear increase in vascular area (R2 = 0.765) and an exponential increase in progenitor cell quantity (R2 = 0.795). Subsequently, quadratic models of vascularity and progenitor cell quantity around the labral clock were used to assess relative healing potential. Quadratic models for percentage vascular area (P = 6.35e-07) and weighted progenitor cell density (P = 3.03e-05) around the labral clock showed that percentage vascular area and progenitor cell quantity increased as labral tissue neared the inferior aspect and diminished near the superior aspect. CONCLUSION:Anatomic regions of the glenoid labrum differ in extracellular matrix composition, vascularity, and cell composition. The superior glenoid labrum is deficient in vascularity and progenitor cells, which may explain the high failure rates for repairs in this location. CLINICAL RELEVANCE:Improved understanding of the composition of distinct glenoid labral positions may help to improve therapeutic strategies for labral pathology.

Purpose The purpose of this historical review is to illustrate the progression and evolution of treatment for distal femur fractures. Methods Scientific literature was searched for descriptions of treatment for distal femur fractures to provide an in-depth overview of the topic, with emphasis on the evolution of surgical constructs used to treat these fractures. Results Prior to the 1950s, distal femur fractures were treated nonoperatively, resulting in considerable morbidity, limb deformity, and limited function. As principles of surgical intervention for fractures emerged in the 1950s, surgeons developed conventional straight plates to better stabilize distal femur fractures. Angle blade plates and dynamic condylar screws emerged out of this scaffolding to prevent post-treatment varus collapse. Meanwhile, intramedullary nails, and later, in the 1990s, locking screws, were introduced to minimize soft tissue disruption. Treatment failure led to the development of locking compression plates with the advantage of accommodating either locking or nonlocking screws. Despite this advancement, the rare but significant incidence of nonunion has not been eliminated, leading to the recognition of the biomechanical environment as important for prevention and the development of active plating techniques. Conclusion Emphasis for the surgical treatment of distal femur fractures has incrementally progressed over time, with initial focus on complete stabilization of the fracture while the biological environment surrounding the fracture was ignored. Techniques slowly evolved to minimize soft tissue disruption, allow more ease of implant placement at the fracture site, and attend to the systemic health of the patient, while simultaneously ensuring appropriate fracture fixation. Through this dynamic process, the desired results of complete fracture healing and maximization of functional outcomes have emerged.

Glenoid labral tears occur with repetitive dislocation events and are common injuries observed in shoulder arthroscopic procedures. Although surgery can restore shoulder anatomy, repair is associated with poor clinical outcomes, which may be attributed to the poor regenerative capability of glenoid labral fibrocartilage. Thus, this study was designed to assess whether in situ tissue regeneration via biomolecule‐stimulated recruitment of progenitor cells is a viable approach for the regeneration of labral tears. We developed a click chemistry‐based bioadhesive to improve labral repair and reduce local inflammatory responses due to trauma. Additionally, we previously identified the presence of progenitor cells in the human labrum, which can be recruited by platelet‐derived growth factor (PDGF). Thus, we hypothesized that PDGF‐releasing adhesives could induce the regenerative responses of progenitor cells at the injury site to improve labral healing. In a rat glenoid labral tear model, we evaluated the effect of PDGF‐releasing adhesives on promoting progenitor cells to participate in labral tear healing. After 3 and 6 weeks, the labrum was histologically analyzed for inflammatory responses, progenitor cell recruitment, proliferation, and extracellular matrix (ECM) production (collagen and glycosaminoglycan). Our results showed that adhesives alone considerably reduced local inflammatory responses and labral tissue dissolution. PDGF‐releasing adhesives significantly increased progenitor cell recruitment, proliferation, and ECM production. These results demonstrate that by accelerating autologous progenitor cell responses, PDGF‐releasing adhesives represent a novel clinically relevant strategy to improve the healing of glenoid labral tears.

Currently, there are no effective clinical or experimental treatments to fully restore the function of the torn acetabular labrum. To fill the gap, here, we report the finding of progenitor cells in labral tissue, which can be recruited and stimulated to repair torn acetabular labral tissue. This study aimed to develop a biomolecule releasing bioadhesive which can speed up labral tissue healing by eliciting autologous labral progenitor cellular responses. A click chemistry-based bioadhesive, capable of releasing biomolecules, was synthesized to exert ~3× adhesion strength compared with fibrin glue. Via the release of platelet-derived growth factor (PDGF), the adhesive was shown to actively recruit and stimulate the proliferation of labral progenitor cells to the tear sites and within the adhesive. Finally, the ability of this biomolecules-releasing adhesive designed to promote labral tissue regeneration was evaluated using discarded human acetabular labrum tissue compared with surgical suture ex vivo. Histological analysis shows that PDGF-releasing bioadhesive yielded significantly more labrum cell responses and extracellular matrix protein (proteoglycan and collagen) production at the tear tissue site than surgical suture controls. The results confirm that the new PDGF-releasing bioadhesive can activate the responses of autologous labral progenitor cells to significantly improve labral tissue regeneration. Clinical significance: These PDGF-releasing bioadhesives may serve as a new and effective tool for repairing and regenerating acetabular labrum tears.

The development of compartment syndrome involving the lower limb is a potentially devastating complication of prolonged surgery in patients held in the lithotomy position. Well leg compartment syndrome (WLCS) was recognized in 1953. The incidence of this condition has been reported to range from 0.20% to 0.03%. The mechanism of WLCS development in the absence of trauma appears to be related to prolonged hypoperfusion of the limb, pressure on the muscle compartments, and in some cases, reperfusion of the ischemic limb. This grave complication develops either during or immediately after prolonged surgery in which the patient was held in the Lloyd-Davies lithotomy or hemi-lithotomy position. Surgeons must be aware of the potential for WLCS development during prolonged surgery. Signs of developing WLCS include swelling, increased firmness of the muscle compartments, discoloration, and cooling of the limb. Preventive measures can be taken without contaminating the surgical field by returning the limb to the right atrium level. Once the diagnosis has been made, failure to prevent the development of WLCS requires extensile fasciotomy of each leg compartment to restore perfusion and relieve elevated intra-compartment pressures. This article reviews the pathophysiology, prevention, and treatment of WLCS.

Fracture healing is a complex cascade of cellular and molecular processes. These processes require the appropriate cellular and molecular environment to ensure the restoration of skeletal stability and resolution of inflammation. In order for fracture healing to occur, the necessary building blocks for bone metabolism and synthesis must be supplied through proper nutrition. Pharmacologic therapies aimed at modulating the inflammatory response to fractures have the potential to interfere with the synthesis of molecules needed for the production of bone. Infection can interfere with, and even prevent normal fracture healing from occurring. Cellular and genetic treatment strategies are actively being developed to target deficiencies, and bridge gaps that can influence how fractures heal. Evolving technologies, including nutritional supplementation, pharmacotherapies, antibiotics, surgical techniques, as well as genetic and cellular therapies, have the potential to enhance, optimize, and even revolutionize the process of fracture healing.

A fraction of the OA patient population is affected by post-traumatic osteoarthritis (PTOA) following acute joint injuries. Stopping or reversing the progression of PTOA following joint injury could improve long-term functional outcomes, reduced disability, and medical costs. To more effectively treat articular cartilage injury, we have developed a novel cell-based therapy that involves the pre-targeting of apoptotic chondrocytes and the delivery of healthy, metabolically active chondrocytes using click chemistry. Specifically, a pre-targeting agent was prepared via conjugating apoptotic binding peptide (ApoPep-1) and trans-cyclooctene (TCO) onto polyethylene glycol (PEG) polymer carrier. The pre-targeting agent would be introduced to injured areas of articular cartilage, leading to the accumulation of TCO groups on the injured areas from actively binding to apoptotic chondrocytes. Subsequently, methyltetrazine (Tz)-bearing chondrocytes would be immobilized on the surface of TCO-coated injured cartilage via Tz-TCO click chemistry reaction. Using an ex vivo human cartilage explant PTOA model, the effectiveness of this new approach was evaluated. Our studies show that this novel approach (Tz-TCO click chemistry) significantly enhanced the immobilization of healthy and metabolically active chondrocytes to the areas of apoptotic chondrocytes. Histological analyses demonstrated that this treatment regimen would significantly reduce the area of cartilage degeneration and enhance ECM regeneration. The results support that Tz-TCO click chemistry-mediated cell delivery approach has great potential in clinical applications for targeting and treatment of cartilage injury.

Cartilage injury affects millions of people throughout the world, and at this time there is no cure. While transplantation of stem cells has shown some success in the treatment of injured cartilage, such treatment is limited by limited cell sources and safety concerns. To overcome these drawbacks, a microscaffolds system was developed capable of targeting, reducing the inflammatory response and recruiting endogenous progenitor cells to cartilage-defect. Erythropoietin (EPO)-loaded-hyaluronic acid (HA) microscaffolds (HA + EPO) were fabricated and characterized. HA-microscaffolds showed good cell-compatibility and could target chondrocytes via CD44 receptors. HA + EPO was designed to slowly release EPO while recruiting progenitor cells. Finally, the ability of HA + EPO to repair cartilage-defects was assessed using a rabbit model of full-thickness cartilage-defect. Our results showed that the intra-articular administration of EPO, HA, and EPO + HA reduced the number of inflammatory cells inside the synovial-fluid, while EPO + HA had the greatest anti-inflammatory effects. Furthermore, among all groups, EPO + HA achieved the greatest progenitor cell recruitment and subsequent chondrogenesis. The results of this work support that, by targeting and localizing the release of growth-factors, HA + EPO can reduce inflammatory responses and promote progenitor cells responses. This new platform represents an alternative treatment to stem-cell transplantation for the treatment of cartilage injury.

The goals of all orthopaedic surgeons treating articular cartilage injuries have been anatomic reduction and stable fixation of the articular cartilage surface with restoration of limb alignment and/or reestablishment of the joint stability, all while minimizing the risk of surgical complications. Recent developments in the study of articular cartilage injury have shown that there is a robust cellular response to joint injury. This response has been shown to involve the synoviocytes, chondrocytes, and osteocytes in and around the injured joint and if these responses are left unchecked, they can lead to the development of posttraumatic osteoarthritis (PTOA). Therefore, to predictably and successfully treat articular cartilage injuries, it is not sufficient to just restore articular congruity, limb alignment, and joint stability, but we must also recognize and attempt to mitigate this associated cellular response. Understanding not only the mechanical aspects of these joint injuries but also the biological aspects is paramount to giving our patients the best opportunity to heal their injuries, recover full function, and avoid the potential devastating development of PTOA. Gone is the simplistic view that if one can achieve articular congruity after intraarticular fracture, as well as joint stability after ligamentous injury, that our patients will do just fine. This review sheds new light on the molecular response to cartilage injury, how residual joint incongruity and instability affect the joint's ability to recover from injury, and how chondrocyte apoptosis in response to injury can influence joint. This article then briefly reviews how cellular and growth factors may be beneficial to the treatment of articular cartilage injury and how ultimately cartilage regeneration may be used in the future to salvage the joints ravaged by PTOA in response to injury.

Objectives: To determine whether the administration of medication for posttraumatic stress disorder (PTSD) to injured trauma survivors prevents or mitigates PTSD. Design: Double-blinded, placebo-controlled. Setting: Level I trauma center. Patients: One hundred twenty patients admitted for traumatic orthopaedic injury. Intervention: Either paroxetine or placebo starting 2 weeks postinjury. Main Outcome Measurements: PTSD symptoms were measured with the PTSD Checklist for DSM-IV. The Quick Inventory of Depressive Symptomatology (QIDS) assessed the presence and severity of DSM-IV-TR major depressive symptoms. The SF-36 measured postinjury quality of life and social functioning. The Short Musculoskeletal Functional Assessment rated postinjury musculoskeletal function. Results: The paroxetine group did not differ from the placebo group in proportions with PTSD as assessed at the 6- or 12-month follow-up or in proportions with major depression symptoms since the injury as assessed at the 3-month follow-up. The groups also did not differ at the 8-week follow-up in the amount of change from baseline in QIDS scores. The paroxetine group had a marginally greater increase from baseline in SF-36 functioning score at the 12-month follow-up as compared with the placebo group and a marginally greater reduction from baseline in Short Musculoskeletal Functional Assessment musculoskeletal functioning at the 12-month follow-up as compared with the placebo group. Conclusions: These results suggest the potential for psychotropic medication to prevent or reduce posttraumatic stress symptoms and to improve the function and health of trauma patients. Further research is needed to confirm paroxetine's use for this purpose. Level of Evidence: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

Ongoing studies investigating fracture healing have uncovered and allowed investigators to gain a better understanding of where the variety of cells, which participate in this process, originate, and how they communicate as well as how they can be enhanced to successfully heal a fracture when the process has slowed or failed completely. This brief review will highlight some of the recent findings regarding the role the immune system in fracture healing and how these cells communicate with each other during the healing process. In addition, two 2 methods that have recently been shown to be promising techniques in supporting fracture when it stalls or reversing the process, when the fracture has failed to heal, will also be described.

Treatment of bone defects remains a challenging clinical problem. Despite our better understanding of bone repair mechanisms and advances made in microsurgical techniques and regenerative medicine, the reintervention rates and morbidity remain high. Surgical techniques such as allograft implantation, free vascularized fibular graft, distraction osteogenesis, loaded titanium cages, and the induced membrane technique continue to evolve, but the outcome can be affected by a number of parameters including the age of the patient, comorbidities, systemic disorders, the location of the defect, and the surgeon's preference and experience. In the herein article, a brief summary of the most currently used techniques for the management of bone defects is presented.

The United States spends more per capita on health care than any other nation, even other high-income countries.1 However, despite its higher spending, the United States performs poorly in areas such as health care coverage and health outcomes.2 This greater spending without commensurate better outcomes has been a strong impetus for health care (payment) reform in the United States. Popular opinion among US legislatures and many physicians has been that the US fee-for-service system is a primary factor for our expensive care and limited outcomes. Many strongly feel that our fee-for-service system leads directly to the overuse of medical services, fragmented care, and an underinvestment in social services.3,4 Given that other high-income countries are apparently able to spend less and achieve better outcomes, there is a strong push in the United States for a better, data-driven understanding of all aspects of health care costs to assist in a logical and effective reform of the current US health care system. Value-based payment strategies, including episode-of-care or bundled payments, have been proposed and are being implemented in certain areas of our health care environment, including orthopaedic surgery, as a mechanism to improve quality of care and reduce the costs of care. Bundled payments have been introduced for total joint arthroplasty and were designed to incentivize greater communication between physicians and other health care providers, and increase coordination among providers across the continuum of care.5,6 These value-based payment models are intended to shift the financial incentives away from volume and toward quality and create an environment where physicians and hospitals share in the financial risks and benefits of cutting costs and improving outcomes. Fromison et al7 published their early results of a bundle payment strategy in improving the quality of care of total joint replacement patients. The Acute Care Episode (ACE) project was a 3-year venture undertaken by Centers for Medicare and Medicaid Services (CMS) between 2009 and 2011. This program provided for bundled payments for hip and knee arthroplasty at 3 US hospitals. Each participating hospital–physician partnership agreed to a percentage discount in diagnosis-related group payment from CMS (∼5%) in return for the ability to gainshare. Specific quality measures were established to which hospitals and physicians needed to comply with to qualify for payment. At the conclusion of the study period, all 3 hospitals were found to have reduced the overall cost per care episode between 10% and 15% while meeting each of the pre-established quality measures. The ACE project demonstrated that it was possible (at least with regards to the treatment of total joint patients) to improve quality and reduce overall costs per episode when surgeons and hospitals collaborate on shared incentives. Althausen and Mead recently published a report outlining their results with value-based total joint arthroplasty program. They reported that participating in the Bundled Payment Care Improvement (BPCI) initiative resulted in a cost savings of $1.6 million in 2015 alone, although they did identify a significant learning curve in doing so.8 Their key findings included appropriate patient selection, strict implant pricing control, adherence to preoperative and postoperative protocols, diligent postcare management, and appropriate choice of metrics to maximize gainsharing potential. Many orthopaedic surgeons in general and orthopaedic trauma surgeons in particular have recognized the train (valued-based payment for medical care) coming down the track, a train that is gathering momentum fueled by the success of BPCI type programs. However, most orthopaedic trauma surgeons astutely recognize that “not all operatively managed patients are the same.” In the lead article in this issue of the Journal of Orthopaedic Trauma, Flanagan et al. have persuasively indicated that the first step in controlling health care expenditures, particularly as it relates to a heterogeneous trauma patient population, is to understand the complete economic profile of these patients as well as the actual costs of their care.9 These investigators have succinctly pointed out that elective surgery patients (ie, total joint patients) enter into the medical system in a vastly different manner and from a different economic standpoint than does the typical acutely injured trauma patient. They make a strong argument that if a bundled payment strategy, designed around a total joint patient population, were to be applied with little allowances for the heterogeneity of trauma patients and their short-term outcomes, as well as their higher post-operative complication rate, it would fail miserably in its efforts to cut costs and improve outcomes. In fact, they showed that doing so would leave hospitals and physicians grossly underfunded and very likely trauma patients less well cared for. For example, the investigators found that uninsured (self-pay) patients represented the largest of their sample's payer class (35.0%), and that 34.5% of the patients were unemployed. Such findings would be unheard of in many if not all private total joint arthroplasty practices. They also found that the Injury Severity Score, longer lengths of stay, and the presence of a complication were positive predictors of overall charges. Again, factors not encountered in the majority of total joint arthroplasty practices. Given these typical scenarios, a bundled payment model would therefore not only proportionately decrease reimbursements for a given episode of care the shortfall in payment would further increase the already high percentage of patients for which the hospital and treating physicians would receive little or no payment. As a result of this experience, it is abundantly clear that in order to create an effective “bundle” for orthopaedic trauma patients the actual cost of care, not only charges and revenue, must be fully understood. Additionally, one must factor in revenue projections for the care of trauma patients related to Disproportionate Share for Hospitals (DHS) payments. These payments where theoretically designed to offset some of the ongoing revenue shortfalls associated with the care of trauma patients. This may however be a mote point, as the Affordable Care Act (ACA) will eliminate DHS payments to all trauma centers, in the very near future. Also, although since the enactment of the ACA more Americans have become insured, this has occurred via Medicaid expansion, which will unfortunately lead to additional shortfalls and a widening of the cost/revenue gap while likely further decreasing professional compensation for those who care for trauma patients. In conclusion, it has been clear for some time that the initial inpatient management of trauma patients is associated with substantial facility and professional charges, which are not even closely covered by the current fee-for-service arrangements. Trauma patients often present without insurance or employment, thus limiting their ability to pay for the cost of their care, while the increase in Medicaid coverage and the loss of DHS funding will only serve to widen this cost/revenue gap. Value-based reimbursement strategies currently being utilized for the reimbursement for services in the care of total joint patients, have not had to address the multitude of issues commonly encountered in the treatment and costs associated with the treatment of trauma patients. Current strategies to reimburse providers based on general population statistics or the total joint replacement population, would not be appropriate for those involved in the treatment of trauma patients. Trauma patients are very heterogeneous group with regard to the spectrum of injury and treatment as well as economic background; thus, a value-based reimbursement system must take these issues into account in order to reduce health care costs and improve outcomes for our trauma patients. Trauma associated investigators, currently working to develop appropriate and objective value based reimbursement strategies in the care of trauma patients, should be commended for their groundbreaking work. The paper by Flanagan et al. should serve as a springboard for other investigations into the creation of fair and effective value-based reimbursement strategies for trauma patients, and serve as a strong warning for us, and legislators, avoid a “one size fits all” approach to orthopaedic trauma care payment reform.

Osteoarthritis is typically caused by cartilage injury, followed by localized inflammatory responses and tissue deterioration. Early treatment of osteoarthritis is often impossible due to the lack of diagnostic options. Recent studies have supported that different imaging probes can be used for arthritis detection in mice. However, none of these diagnostic tools have been tested on human articular cartilage. To fill this gap, an optical imaging probe was developed to target activated macrophages and the accumulation of imaging probes on tissue was used to assess the severity of human osteoarthritis. Methods: The probe was fabricated using hyaluronic acid (HA) particles conjugated with near-infrared dye and folic acid (FA). The ability of the FA-HA probes to detect activated macrophages and quantify cartilage injury was evaluated using a cell culture model in vitro and human osteoarthritic cartilage explants ex vivo. Results: Our cell study results supported that the FA-HA probes are cell compatible (up to 0.5mg/mL) and can detect activated macrophages in 30 minutes. Using human articular cartilage, we verified the existence of activated macrophages on osteoarthritic cartilage with highly up-regulated expression of folate receptors (~13 folds by comparison with healthy control). In addition, we found that FA-HA probes had higher binding amounts (~3 folds) to osteoarthritic tissue than healthy ones. Histological analyses confirmed that there was a strong linear relationship (R=0.933) between the fluorescent intensity of tissue-associated probe and the extent of folate receptors on osteoarthritic cartilage. Finally, the co-localization of the imaging probe, folate receptors and cartilage degeneration on the tissue sections indicated the extraordinary accuracy and efficiency of this osteoarthritis diagnostic probe. Conclusions: Our results support the probe as an effective diagnostic tool to detect the area and severity of osteoarthritic human articular cartilage.