Histological Analysis of Regenerative Properties in Human Glenoid Labral Regions.

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.

Distal femur fractures management and evolution in the last century.

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.

Biomolecule-releasing bioadhesive for glenoid labrum repair through induced host progenitor cell responses.

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.

Well Leg Compartment Syndrome: Pathophysiology, Prevention, and Treatment.

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.

Biomolecules-releasing click chemistry-based bioadhesives for repairing acetabular labrum 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.

Click chemistry-based pre-targeting cell delivery for cartilage regeneration.

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.

Bone healing: Advances in biology and technology.

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.

Recruitment of endogenous progenitor cells by erythropoietin loaded particles for in situ cartilage regeneration.

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.

Understanding Articular Cartilage Injury and Potential Treatments.

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.

Cell-Based Therapies for the Treatment of Fractures.

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.

Prospective Study of the Effectiveness of Paroxetine on the Onset of Posttraumatic Stress Disorder, Depression, and Health and Functional Outcomes After Trauma.

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.

Hyaluronic Acid-Based Optical Probe for the Diagnosis of Human Osteoarthritic Cartilage.

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.

Absolute Versus Relative Fracture Fixation: Impact on Fracture Healing.

The goals of all orthopaedic surgeons treating fractures are, and will remain, obtaining union of the fracture with a well-aligned and functional limb while minimizing the risk of complications. This requires us to understand how the biomechanical environment of the fracture affects healing and to be able to discern which mechanical environment is preferred over another. Understanding the spectrum of stability imparted by our current surgical devices is paramount to giving our patients the best opportunity to heal and recover from their injury. Gone are the simplistic views of plates and screws being applied for absolute stability and nails and external fixators being applied for relative stability. This review sheds new light on how the use of different implants provides the appropriate stability to encourage fracture healing and limit the risk of complication and loss of function.

Fracture Healing Adjuncts-The World's Perspective on What Works.

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.

An optical probe for detecting chondrocyte apoptosis in response to mechanical injury.

Cartilage injury induced by acute excessive contact stress is common and mostly affects young adult. Although early detection of cartilage injury may prevent serious and lifelong arthritic complications, early detection and treatment is not possible due to the lack of a reliable detection method. Since chondrocyte injury and subsequent cell death are the early signs of cartilage injury, it is likely that cartilage cell apoptosis can be used to predict the extent of injury. To test this hypothesis, a near infrared probe was fabricated to have high affinity to apoptotic cells. In vitro tests show that this apoptosis probe has low toxicity, high specificity, and high affinity to apoptotic cells. In addition, there is a positive relationship between apoptotic cell numbers and fluorescence intensities. Using a mouse xiphoid injury model, we found significant accumulation of the apoptosis probes at the injured xiphoid cartilage site. There was also a positive correlation between probe accumulation and the number of apoptotic chondrocytes within the injured xiphoid cartilage, which was confirmed by TUNEL assay. The results support that the apoptosis probes may serve as a powerful tool to monitor the extent of mechanical force-induced cartilage injury in vivo.

Bone Grafting: Sourcing, Timing, Strategies, and Alternatives.

Acute fractures, nonunions, and nonunions with bone defects or osteomyelitis often need bone graft to facilitate union. There are several factors to consider when it is determined that a bone graft is needed. These factors include the source of the bone graft (autograft vs. allograft), proper timing for placement of the bone graft, strategies to avoid further complications (particularly in the setting of osteomyelitis), and with the development of a variety of bone graft substitutes, whether alternatives to autograft are available and appropriate for the task at hand. Autograft bone has commonly been referred to as the "gold standard" of bone grafts, against which the efficacy of other grafts has been measured. The best timing for when to place a bone graft or substitute is also somewhat controversial, particularly after an open fracture or a potentially contaminated bed. The treatment of infected nonunions, particularly those that require a graft to facilitate healing, can be quite challenging. Typically, the infection is completely eradicated before placement of a bone graft, but achieving a sterile bed and the timing of a bone graft require strategic thinking and planning. This review outlines the benefits of autografts, the most suitable sites for harvesting bone grafts, the timing of bone graft procedures, the potential risks and benefits of grafting in the face of infection, and the currently available bone graft extenders.

Articular Cartilage Injury and Potential Remedies.

Osteoarthritis affects millions of people worldwide, is associated with joint stiffness and pain, and often causes significant disability and loss of productivity. Osteoarthritis is believed to occur as a result of ordinary "wear and tear" on joints during the course of normal activities of daily living. Posttraumatic osteoarthritis is a particular subset of osteoarthritis that occurs after a joint injury. Developing clinically relevant animal models will allow investigators to delineate the causes of posttraumatic osteoarthritis and develop means to slow or prevent its development after joint injury. Chondroprotectant compounds, which attack the degenerative pathways at a variety of steps, are being developed in an effort to prevent posttraumatic osteoarthritis and offer great promise. Often times, cartilage degradation after joint injury occurs despite our best efforts. When this happens, there are several evolving techniques that offer at least short-term relief from the effects of posttraumatic osteoarthritis. Occasionally, these traumatic lesions are so large that dramatic steps must be taken in an attempt to restore articular congruity and joint stability. Fresh osteochondral allografts have been used in these settings and offer the possibility of joint preservation. For patients presenting with neglected displaced intra-articular fractures that have healed, intra-articular osteotomy techniques are being developed in an effort to restore joint congruity and function. This article reviews the results of a newly developed animal model of posttraumatic osteoarthritis, several promising chondroprotectant compounds, and also cartilage techniques that are used when degenerative cartilage lesions develop after joint injury.