Cell-Mediated Immune Responses May Play Roles in Osteochondral Allograft Transplantation Osteointegration Failures.

Prolonged and incomplete osteochondral allograft (OCA) osteointegration is consistently cited as a major mechanism for OCA treatment failure. Subrejection immune responses may play roles in this mode of failure. Preimplantation OCA preparation techniques, including subchondral bone drilling, thorough irrigation, and autogenous bone marrow aspirate concentrate saturation, may dampen immune responses and improve OCA osteointegration. This study sought to further characterize potential immune system contributions to OCA transplantation treatment failures by analyzing donor-recipient ABO and Rh-factor mismatches and histological and immunohistochemical assessments of transplanted OCA tissues recovered from revision surgeries. Using a dedicated registry, OCA transplant recipients with documented treatment failures who met inclusion criteria (n = 33) as well as age-, body mass index-, and joint-matched patients with successful outcomes (n = 70) were analyzed to compare matched cohorts of patients with successful versus failed OCA transplantation outcomes. Tissues recovered from 18 failed OCA transplants and portions of 7 nonimplanted OCA controls were further analyzed to provide contributing evidence for potential immune response mechanisms. For patients analyzed, no statistically significant differences in proportions for treatment success versus failure based on mismatches for ABO type, Rh factor, or both were noted. Further, no statistically significant differences in proportions for histological immune response presence or absence based on mismatches for ABO type, Rh factor, or both were noted. Twelve (67%) of the failed OCA tissues contained lymphocyte aggregations in the subchondral bone, which were comprised of combinations of CD3 + , CD4 + , CD8 + , and CD20+ lymphocytes. The mechanisms of failure for these 12 OCA transplants involved insufficient OCA osteointegration. Results of this study suggest that T- and B-cell-mediated subrejection immune responses may play roles in OCA transplant treatment failures independent of donor-recipient blood type mismatch effects.

The osteoarthritis prevention study (TOPS) - A randomized controlled trial of diet and exercise to prevent Knee Osteoarthritis: Design and rationale.

Background: Osteoarthritis (OA), the leading cause of disability among adults, has no cure and is associated with significant comorbidities. The premise of this randomized clinical trial is that, in a population at risk, a 48-month program of dietary weight loss and exercise will result in less incident structural knee OA compared to control. Methods/design: The Osteoarthritis Prevention Study (TOPS) is a Phase III, assessor-blinded, 48-month, parallel 2 arm, multicenter randomized clinical trial designed to reduce the incidence of structural knee OA. The study objective is to assess the effects of a dietary weight loss, exercise, and weight-loss maintenance program in preventing the development of structural knee OA in females at risk for the disease. TOPS will recruit 1230 ambulatory, community dwelling females with obesity (Body Mass Index (BMI) â€‹≥ â€‹30 â€‹kg/m2) and aged ≥50 years with no radiographic (Kellgren-Lawrence grade ≤1) and no magnetic resonance imaging (MRI) evidence of OA in the eligible knee, with no or infrequent knee pain. Incident structural knee OA (defined as tibiofemoral and/or patellofemoral OA on MRI) assessed at 48-months from intervention initiation using the MRI Osteoarthritis Knee Score (MOAKS) is the primary outcome. Secondary outcomes include knee pain, 6-min walk distance, health-related quality of life, knee joint loading during gait, inflammatory biomarkers, and self-efficacy. Cost effectiveness and budgetary impact analyses will determine the value and affordability of this intervention. Discussion: This study will assess the efficacy and cost effectiveness of a dietary weight loss, exercise, and weight-loss maintenance program designed to reduce incident knee OA. Trial registration: ClinicalTrials.gov Identifier: NCT05946044.

Making the Case for Hyperosmolar Saline Arthroscopic Irrigation Fluids: A Systematic Review of Basic Science, Translational, and Clinical Evidence.

Commonly used isotonic arthroscopic irrigation fluids, such as normal saline or lactated Ringer's, were initially formulated for intravenous administration so they do not replicate the physiologic properties of healthy synovial fluid. Synovial fluid plays an important role in regulating joint homeostasis such that even transient disruptions in its composition and physiology can be detrimental. Previous studies suggest that hyperosmolar solutions may be a promising alternative to traditional isotonic fluids. This manuscript sought to systematically review and synthesize previously published basic science, translational, and clinical studies on the use of hyperosmolar arthroscopic irrigation fluids to delineate the optimal fluid for clinical use. A systematic literature search of MEDLINE/PubMed and Embase databases was performed in accordance with Preferred Reporting Items for Systemic Reviews and Meta-analyses (PRISMA) guidelines. The search phrases were: ("cartilage" AND "hyperosmolar"); ("arthroscopy" OR "arthroscopic" AND "hyperosmolar"). The titles, abstracts, and full texts were screened for studies on hyperosmolar solutions and articular cartilage. Study quality was assessed, and relevant data were collected. A meta-analysis was not performed due to study heterogeneity. A risk of bias assessment was performed on the included translational and clinical studies. There were 10 basic science studies, 2 studies performed in translational animal models, and 2 clinical studies included in this review. Of the basic science studies, 7 utilized a mechanical injury model. The translational studies were carried out in the canine shoulder and equine stifle (knee) joint. Clinical studies were performed in the shoulder and knee. Multiple basic science, translational, and clinical studies highlight the short-term safety, cost-effectiveness, and potential benefits associated with use of hyperosmolar solutions for arthroscopic irrigation. Further work is needed to develop and validate the ideal formulation for a hyperosmolar irrigation solution with proven long-term benefits for patients undergoing arthroscopic surgeries.

Evaluation of mechanistic serum and urine biomarkers for secondary osteoarthritis associated with developmental dysplasia of the hip.

Objective: Determine measurable differences for mechanistic urine and serum biomarkers in patients with developmental dysplasia of the hip (DDH) prior to, and following, secondary hip osteoarthritis (OA) when compared to controls. Design: Urine and serum were collected from individuals with developmental dysplasia of the hip (n = 39), prior to (Pre-OA DDH, n = 32) and following diagnosis of secondary hip OA (Post-OA DDH, n = 7), age-matched Pre-OA controls (n = 35), and age-matched Post-OA controls (n = 12). Samples were analyzed for protein biomarkers with potential for differentiation of hip status through a Mann-Whitney U test with a Benjamini-Hochberg correction. Results: Several interleukin and degradation related proteins were found to be differentially expressed when comparing DDH-related hip status prior to and following diagnosis of hip OA. In addition, MCP-1 and TIMP-1 were significantly different between younger and older patients in the control cohorts. Conclusion: These results provide initial evidence for serum and urine protein biomarkers that define clinically relevant stages of symptomatic DDH and its progression to secondary hip osteoarthritis categorized by known mechanisms of disease. Level of evidence: III.

Evaluation of Serum and Urine Biomarker Panels for Developmental Dysplasia of the Hip Prior to Onset of Secondary Osteoarthritis.

OBJECTIVE: Evaluate serum and urine biomarker panels for their capabilities in discriminating between individuals (13- to 34-years-olds) with healthy hips versus those with developmental dysplasia of the hip (DDH) prior to diagnosis of secondary hip osteoarthritis (OA). DESIGN: Urine and serum were collected from individuals (15-33 years old) with DDH, prior to and following diagnosis of hip OA, and from age-matched healthy-hip controls. Samples were analyzed for panels of protein biomarkers with potential for differentiation of hip status using receiver operator characteristic curve (area under curve [AUC]) assessments. RESULTS: Multiple urine and serum biomarker panels effectively differentiated individuals with DDH from healthy-hip controls in a population at risk for developing secondary hip OA with the best performing panel demonstrating an AUC of 0.959. The panel comprised of two serum and two urinary biomarkers provided the highest combined values for sensitivity, 0.85, and specificity, 1.00, while a panel of four serum biomarkers provided the highest sensitivity, 0.93, while maintaining adequate specificity, 0.71. CONCLUSION: Results of this study indicate that panels of protein biomarkers measured in urine and serum may be able to differentiate young adults with DDH from young adults with healthy hips. These data suggest the potential for clinical application of a routine diagnostic method for cost-effective and timely screening for DDH in at-risk populations. Further development and validation of these biomarker panels may result in highly sensitive and specific tools for early diagnosis, staging, and prognostication of DDH, as well as treatment decision making and monitoring capabilities. LEVEL OF EVIDENCE: III.

Biologic Joint Restoration: A Translational Research Success Story.

Treatment options that result in consistently successful outcomes for young and active patients with joint disorders are needed. This article summarizes two decades of rigorous research using a bedside-to-bench- to-bedside translational approach based on the One Health - One Medicine concept that culminated in successful clinical use of biologic joint restoration options for treatment of knee, hip, ankle, and shoulder problems in this growing patient population.

The use of a hyperosmolar irrigation solution is safe in an equine stifle joint model but does not reduce joint swelling.

OBJECTIVE: To determine the following: (1) whether an irrigation solution that is hyperosmolar (HYPER) relative to synovial fluid decreases tissue extravasation during an arthroscopic protocol when compared to a relatively hypoosmolar solution, (2) the safety of a HYPER solution based on viability of joint tissues following joint irrigation, and (3) if the use of a HYPER solution decreases water content in stifle joint tissue. ANIMALS: 8 adult horses. PROCEDURES: A prospective, blinded, randomized controlled trial was performed to compare lactated Ringer's solution (LRS; 273 mOsm/L) and a HYPER (600 mOsm/L) irrigation solution for routine medial femorotibial joint (MFTJ) arthroscopy. Primary outcomes included quantification of periarticular fluid retention based on measured changes in defined stifle joint girth and ultrasonographic (US) criteria. Water content of tissue samples was assessed. The viability of articular cartilage was determined using a microscopic fluorescent cell viability staining system. RESULTS: No significant difference in postprocedural joint swelling was observed between LRS and HYPER treatment groups. Percent increments in femorotibial joint dimensions (mean ± SD) were seen in both treatment groups based on US (LRS, 83.9 ± 84.6%; HYPER, 131.2 ± 144.9%) and caliper measurements (LRS 5.5 ± 4.3%; HYPER 7.5 ± 5.8%) (P ≤ .05). Chondrocyte viability and tissue water content were maintained in both treatment groups, and differences were not statistically significant. CLINICAL RELEVANCE: Doubling the osmolarity of an irrigation solution used routinely for arthroscopy does not result in detrimental effects on chondrocyte viability or tissue water content. However, use of a relatively HYPER irrigation solution did not attenuate procedural tissue swelling of the equine stifle joint.

Treatment-Monitoring Capabilities of Serum and Urine Biomarkers for Meniscal Allograft Transplantation in a Preclinical Canine Model.

BACKGROUND: Meniscal allograft transplantation (MAT) has been developed as a treatment for meniscal deficiency. Despite promising outcomes, there are no real-time methods to evaluate graft survivorship and predict functional outcomes. HYPOTHESIS: Assessment of serum and urine biomarkers could be used to develop biomarker panels-prognostic (1- and 3-month postsurgical time points) and diagnostic (6-month time point)-based on strong associations with clinically relevant outcome metrics obtained 6 months after surgery. STUDY DESIGN: Descriptive laboratory study. METHODS: Twelve adult purpose-bred research hounds were included and underwent medial meniscal release to induce meniscal deficiency. Three months after meniscal release surgery, medial menisci were replaced with fresh-frozen meniscus (n = 4), fresh meniscus (n = 4), or fresh meniscotibial osteochondral allograft (n = 4) such that a spectrum of pain and functional outcomes could be anticipated. Serum and urine from all dogs were collected preoperatively and at 1, 3, and 6 months after MAT surgery. Dogs were assessed for pain-related and functional outcomes at the same time points. To develop a prognostic panel of biomarkers, biomarker data from the 1- and 3-month post-MAT surgery time points were used to model 6-month clinical outcomes. A diagnostic panel of biomarkers was developed using data from the 6-month post-MAT surgery to model 6-month clinical outcomes. Primary outcomes for pain and function were visual analog scale (VAS) and operated limb percentage total pressure index (%TPI), respectively. Using random subject effects, linear mixed models were used to develop prognostic biomarker panels, and linear fixed-effect models were used to develop diagnostic biomarker panels, with variance explained for each panel reported (R2) along with individual biomarker relationships. RESULTS: Across prognostic biomarker panels, a panel including serum IL-6, IL-8, IL-10, and IL-18 was fit for the primary functional outcome, operated limb %TPI (R2 = 0.450), whereas a panel including serum CTX-II and OPG was fit for the primary pain-related outcome, VAS (R2 = 0.516). Across diagnostic biomarker panels, a panel including serum MMP-1 and MMP-3 and urine PINP and TIMP-1 was fit for %TPI (R2 = 0.863). Separately, a panel including urine CTX-I, CTX-II, IL-8, MMP-2, and TIMP-1 was fit as diagnostic biomarkers for the VAS for pain (R2 = 0.438). CONCLUSION: Biomarker panels of selected serum and/or urine proteins can model clinically relevant metrics for function and pain in a preclinical model of MAT. CLINICAL RELEVANCE: Biomarker panels could be used to provide real-time diagnostic and prognostic data regarding outcomes after MAT.

Small laboratory animal models of anterior cruciate ligament reconstruction.

Anterior cruciate ligament (ACL) injuries are common knee ligament injuries. While generally successful, ACL reconstruction that uses a tendon graft to stabilize the knee is still associated with a notable percentage of failures and long-term morbidities. Preclinical research that uses small laboratory species (i.e., mice, rats, and rabbits) to model ACL reconstruction are important to evaluate factors that can impact graft incorporation or posttraumatic osteoarthritis after ACL reconstruction. Small animal ACL reconstruction models are also used for proof-of-concept studies for the development of emerging biological strategies aimed at improving ACL reconstruction healing. The objective of this review is to provide an overview on the use of common small animal laboratory species to model ACL reconstruction. The review includes a discussion on comparative knee anatomy, technical considerations including types of tendon grafts employed amongst the small laboratory species (i.e., mice, rats, and rabbits), and common laboratory evaluative methods used to study healing and outcomes after ACL reconstruction in small laboratory animals. The review will also highlight common research questions addressed with small animal models of ACL reconstruction.

Effects of Caffeine on Intervertebral Disc Cell Viability in a Whole Organ Culture Model.

STUDY DESIGN: Controlled laboratory study. OBJECTIVE: To investigate the impact of exposure to physiologically relevant caffeine concentrations on intervertebral disc (IVD) cell viability and extracellular matrix composition (ECM) in a whole organ culture model as potential contributing mechanisms in development and progression of IVD disorders in humans. Primary outcome measures were IVD viable cell density (VCD) and ECM composition. METHODS: A total of 190 IVD whole organ explants from tails of 16 skeletally mature rats-consisting of cranial body half, endplate, IVD, endplate, and caudal body half-were harvested. IVD explants were randomly assigned to 1 of 2 groups: uninjured (n = 90) or injured (20G needle disc puncture/aspiration method, n = 100). Explants from each group were randomly assigned to 1 of 3 treatment groups: low caffeine (LCAF: 5 mg/L), moderate caffeine (MCAF: 10 mg/L), and high caffeine (HCAF: 15 mg/L) concentrations. RESULTS: Cell viability was significantly higher in the low-caffeine group compared with the high-caffeine group at day 7 (P = .037) and in the low-caffeine group compared with the medium- and high-caffeine groups at day 21 (P ≤ .004). Analysis of ECM showed that all uninjured and control groups had significantly higher (P < .05) glycosaminoglycan concentrations compared with all injured groups. Furthermore, we observed a temporal, downward trend in proteoglycan to collagen ratio for the caffeine groups. CONCLUSIONS: Caffeine intake may be a risk factor for IVD degeneration, especially in conjunction with disc injury. Mechanisms for caffeine associated disc degeneration may involve cell and ECM, and further studies should elucidate mechanistic pathways and potential benefits for caffeine restriction.

Acute Physiological Effects of Continuous Versus Intermittent Walking During Golf in Individuals With Knee Osteoarthritis: A Pilot Study.

OBJECTIVE: The aim of the study was to compare the acute effects of walking the golf course versus using a golf cart during a round of golf on biological markers of joint disease, joint pain, and cardiovascular parameters in individuals with knee osteoarthritis. METHODS: Participants with knee OA (n = 10) older than 50 yrs were recruited for this crossover designed study in which they completed two 18-hole rounds of golf: (1) walking the course and (2) using a golf cart. Five control participants (n = 5) performed the walking condition only. Step count, heart rate, rating of perceived exertion and pain using the Numeric Pain Rating Scale were measured during the round. Serum was collected at baseline, 9th hole (halfway), and 18th hole (completion) and tested for biomarkers associated with tissue turnover (cartilage oligomeric matrix protein), inflammation (tumor necrosis factor α, interleukin 1ß, interleukin 6), and degradative enzyme production (matrix metalloproteinase 3, matrix metalloproteinase 13). RESULTS: In knee OA participants, walking the course was associated with significantly higher step count and duration of moderate/vigorous physical activity (72.2% vs. 32.6% of the round) but did lead to a significant increase in knee joint pain (P < 0.05). Both conditions caused cartilage oligomeric matrix protein and matrix metalloproteinase 13 concentration increases from baseline to completion (P < 0.05), but inflammatory markers (tumor necrosis factor α, interleukin 6, and interleukin 1ß, P < 0.05) only increased when walking the course. Biomarker concentrations did not increase in control participants. CONCLUSIONS: Walking the course optimizes the duration of moderate/vigorous activity during a round of golf, but the golf cart is a beneficial option in those with exacerbated joint pain and inflammation that would otherwise limit participation.

A prospective randomized double-blind clinical trial to assess the effects of leukocyte-reduced platelet-rich plasma on pro-inflammatory, degradative, and anabolic biomarkers after closed pilon fractures.

Posttraumatic osteoarthritis (PTOA) significantly affects patients with pilon fractures even after adequate anatomical reduction, and treatment strategies targeting the biologic mediators of PTOA are needed. This study was designed to determine the effects of intra-articular injection of platelet-rich plasma (PRP) on synovial fluid (SF) biomarkers for patients undergoing open reduction and internal fixation (ORIF) of pilon fractures. Patients undergoing staged management of pilon fractures were enrolled in a prospective, double-blinded, randomized, and placebo-controlled clinical trial to determine the effects of a single intra-articular injection of leukocyte-reduced PRP on SF biomarkers. Arthrocentesis of the injured and uninjured ankles was performed at the time of external skeletal fixation (ESF) and ORIF. Patients were randomized to receive either autogenous leukocyte-reduced PRP or saline (control) via intra-articular injection into the injured ankle at the time of ESF. SF biomarker concentrations were compared-uninjured, injured pretreatment, and saline-injected or PRP-injected. Eleven patients (PRP, n = 5; saline, n = 6) completed the study. Twenty-one uninjured, and 11 injured pretreatment, five PRP-treated, and six saline-treated SF samples were analyzed. PRP-treated SF contained significantly higher levels of PDGF-AA (p = 0.046) and significantly lower levels of MMP-3 (p = 0.042), MMP-9 (p = 0.009), IL-1ß (p = 0.049), IL-6 (p < 0.01), IL-8 (p = 0.048), and PGE2 (p < 0.04). This study provided mechanistic data to suggest that a single intraarticular injection of leukocyte-reduced PRP is associated with anti-inflammatory, anti-degradative, and anabolic responses compared with saline control. These findings provide the impetus for investigating long-term clinical outcomes after PRP injection as an orthobiologic adjunct to ORIF for mitigating the incidence and severity of PTOA after pilon fractures.

An Injectable Containing Morphine, Ropivacaine, Epinephrine, and Ketorolac Is Not Cytotoxic to Articular Cartilage Explants From Degenerative Knees.

PURPOSE: The purpose of this study was to determine the effects of a multidrug injectate containing morphine, ropivacaine, epinephrine, and ketorolac, commonly referred to as the "Orthococktail," on cartilage tissue viability and metabolic responses using an established in vitro model. METHODS: With institutional review board approval and informed patient consent, tissues normally discarded after total knee arthroplasty (TKA) were recovered. Full-thickness cartilage explants (n = 72, Outerbridge grade 1 to 3) were created and bisected. Paired explant halves were treated with either 1 mL Orthococktail or 1 mL of saline and cultured for 8 hours at 37°C, with 0.5 mL of the treatment being removed and replaced with tissue culture media every hour. Explants were cultured for 6 days, and media were changed and collected on days 3 and 6. After day 6, tissues were processed for cell viability, weighed, and processed for histologic grading. Outcome measures were compared for significant differences between treated and untreated samples. RESULTS: There were no significant differences in cartilage viability between control and Orthococktail-treated samples across a spectrum of cartilage pathologies. Orthococktail treatment consistently resulted in a significant decrease in the release of PGE2, MCP-1, MMP-7, and MMP-8 on day 3 of culture and PGE2, MMP-3, MMP-7, and MMP-8 on day 6 of culture, compared with saline controls. CONCLUSION: The results of the present study indicate that an Orthococktail injection composed of morphine, ropivacaine, epinephrine, and ketorolac is associated with a transient decrease in degradative and inflammatory mediators produced by more severely affected articular cartilage and may mitigate perioperative joint pain such that postoperative narcotic drug use could be reduced. CLINICAL RELEVANCE: The Orthococktail solution used in this study may be a safe intraoperative, intra-articular injection option for patients undergoing joint arthroplasty and other joint preservation surgical procedures.

Bacterial DNA screening to characterize surgical site infection risk in orthopaedic patients.

PURPOSE: To provide an initial characterization of relevant bacterial DNA profiles for patients undergoing closed-fracture fixation or total joint arthroplasties. PATIENTS AND METHODS: Swabs were collected and analyzed using Polymerase Chain Reaction from adult patients undergoing closed-fracture fixation or total shoulder, knee, or hip arthroplasties. RESULTS: Bacterial DNA profiles varied across the different orthopaedic patient populations, and produced uncharacteristic profile shifts with direct relevance to each clinical infection. CONCLUSION: Findings provide a foundational dataset regarding bacterial colonization of relevant anatomic sites that can act as sources of surgical site infections for patients.

Reamer-irrigator-aspirate versus bone marrow aspirate concentrate for osteoprogenitor cell retention and osteoinductive protein release on cancellous bone.

Bone defects often require operative intervention with the use of bone graft. Two sources of autologous bone graft include reamer-irrigator-aspirate (RIA) and bone marrow aspirate concentrate (BMC). Osteoprogenitor cells and osteoconductive proteins have been identified in both sources. This study collected samples of these cells and proteins from a canine model and cultured them on human cancellous allograft bone blocks. Findings suggest that BMC may be preferred for indications that allow for delivery via injection, saturation of the patient's tissues, or an implanted scaffold, whereas RIA may be preferred when the biologic augment is delivered as a scaffold or graft.

A Hyperosmolar Saline Solution Fortified with Anti-Inflammatory Components Mitigates Articular Cartilage Pro-Inflammatory and Degradative Responses in an In Vitro Model of Knee Arthroscopy.

OBJECTIVE: To evaluate differences in pro-inflammatory and degradative mediator production from osteoarthritic knee articular cartilage explants treated with a hyperosmolar saline solution supplemented with anti-inflammatory components (l-glutamine, ascorbic acid, sodium pyruvate, epigallocatechin gallate [EGCG], and dexamethasone) or normal saline using an in vitro model for knee arthroscopy. DESIGN: Full-thickness 6 mm articular cartilage explants (n = 12/patient) were created from femoral condyle and tibial plateau samples collected from patients who received knee arthroplasty. One explant half was treated for 3 hours with hyperosmolar saline (600 mOsm/L) supplemented with anti-inflammatory components and the corresponding half with normal saline (308 mOsm/L). Explants were cultured for 3 days and then collected for biomarker analyses. Media biomarker concentrations were normalized to the wet weight of the tissue (mg) and were analyzed by a paired t test with significance set at P < 0.05. RESULTS: Cartilage was collected from 9 females and 2 males (mean age = 68 years). Concentrations of MCP-1 (P < 0.001), IL-8 (P = 0.03), GRO-α (P = 0.02), MMP-1 (P < 0.001), MMP-2 (P < 0.001), and MMP-3 (P < 0.001) were significantly lower in explant halves treated with the enhanced hyperosmolar solution. When considering only those cartilage explants in the top tercile of tissue metabolism, IL-6 (P = 0.005), IL-8 (P = 0.0001), MCP-1 (P < 0.001), GRO-α (P = 0.0003), MMP-1 (P < 0.001), MMP-2 (P < 0.001), MMP-3 (P < 0.001), and GAG expression (P = 0.0001) was significantly lower in cartilage explant halves treated with the enhanced hyperosmolar solution. CONCLUSIONS: Treatment of cartilage explants with a hyperosmolar saline arthroscopic irrigation solution supplemented with anti-inflammatory components was associated with significant decreases in inflammatory and degradative mediator production and mitigation of proteoglycan loss.

Systematic Review of Osteochondral Allograft Transplant Immunology: How We Can Further Optimize Outcomes.

Despite the growing success for osteochondral allograft (OCA) transplantation in treating large articular cartilage lesions in multiple joints, associated revision and failure rates are still higher than desired. While immunorejection responses have not been documented, the effects of the host's immune responses on OCA transplantation failures have not been thoroughly characterized. The objective of this study was to systematically review clinically relevant peer-reviewed evidence pertaining to the immunology of OCAs to elucidate theragnostic strategies for improving functional graft survival and outcomes for patients undergoing OCA transplantation. This systematic review of Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, MEDLINE, PubMed, and EMBASE suggests that host immune responses play key roles in incorporation and functional survival of OCA transplants. OCA rejection has not been reported; however, graft integration through creeping substitution is reliant on host immune responses. Prolonged inflammation, diminished osteogenic potential for healing and incorporation, and relative bioburden are mechanisms that may be influenced by the immune system and contribute to undesirable outcomes after OCA transplantation. Based on the safety and efficacy of OCA transplantation and its associated benefits to a large and growing patient population, basic, preclinical, and clinical osteoimmunological studies on OCA transplantation that comprehensively assess and correlate cellular, molecular, histologic, biomechanical, biomarkers, diagnostic imaging, arthroscopic, functional, and patient-reported outcome measures are of high interest and importance.

Effects of cyclic compression on intervertebral disc metabolism using a whole-organ rat tail model.

Many factors contribute to the development and progression of intervertebral disc (IVD) degeneration. This study was designed to assess the effects of compressive load magnitude on IVD metabolism. It was hypothesized that as load magnitude increased, there would be a significant increase in release of proinflammatory and degradative biomarkers, and a significant decrease in tissue proteoglycan (GAG) and collagen contents compared with unloaded controls. IVD whole organ functional spinal units (FSU) consisting of cranial and caudal body halves, cartilage endplates, and IVD (n = 36) were harvested from the tails of six Sprague Dawley rats, and FSUs were cultured at 0.0 MPa, 0.5 MPa, or 1.0 MPa at 0.5 Hz for 3 days. After culture, media were collected for biomarker analysis and FSUs were analyzed for extracellular matrix composition. Significant differences were determined using a one-way analysis of variance or Kruskal-Wallis test and post hoc analyses. Media concentrations of IFN-γ, IL-6, IL-1ß, and MMP-8 were significantly higher in the 0.5 MPa compared with the 0.0 MPa group. Media concentrations of PGE2 and TIMP-1 were significantly higher in the 1.0 MPa group compared with the 0.0 MPa group, and media PGE2 was significantly higher in the 1.0 MPa group compared with the 0.5 MPa group. Media GAG content was significantly higher in the 1.0 MPa group compared with the 0.0 MPa group, and percent GAG in the tissue was significantly lower in 0.5 MPa and 1.0 MPa groups compared with the 0.0 MPa group. Clinical Significance: These data suggest that there are magnitude-dependent inflammatory and degradative IVD responses to cyclic loading, which may contribute to IVD degeneration.

Comparison of meniscal allograft transplantation techniques using a preclinical canine model.

Meniscal allograft transplantation (MAT) can be a safe, effective treatment for meniscal deficiency resulting in knee dysfunction, leading to osteoarthritis (OA) without proper treatment with 5-year functional success rates (75%-90%). While different grafts and techniques have generally proven safe and effective, complications include shrinkage, extrusion, progression of joint pathology, and failure. The objective of this study was to assess the functional outcomes after MAT using three different clinically-relevant methods in a preclinical canine model. The study was designed to test the hypothesis that fresh meniscal-osteochondral allograft transplantation would be associated with significantly better function and joint health compared with fresh-viable or fresh-frozen meniscus-only allograft transplantations. Three months after meniscal release to induce meniscus-deficient medial compartment disease, research hounds (n = 12) underwent MAT using meniscus allografts harvested from matched dogs. Three MAT conditions (n = 4 each) were compared: frozen meniscus-fresh-frozen meniscal allograft with menisco-capsular suture repair; fresh meniscus-fresh viable meniscal allograft (Missouri Osteochondral Preservation System (MOPS)-preservation for 30 days) with menisco-tibial ligament repair; fresh menisco-tibial-fresh, viable meniscal-tibial-osteochondral allografts (MOPS-preservation for 30 days) with menisco-tibial ligament preservation and autogenous bone marrow aspirate concentrate on OCA bone. Assessment was performed up to 6 months after MAT. Pain, comfortable range of motion, imaging, and arthroscopic scores as well histological and cell viability findings were superior (P < .05) for the fresh menisco-tibial group compared with the two other groups. Novel meniscal preservation and implantation techniques with fresh, MOPS-preserved, viable meniscal-osteochondral allografts with menisco-tibial ligament preservation appears to be safe and effective for restoring knee function and joint health in this preclinical model. This has the potential to significantly improve outcomes after MAT.

Outcomes Associated With Osteochondral Allograft Transplantation in Dogs.

The purpose of this study was to retrospectively characterize outcomes and complications associated with osteochondral allograft transplantation for treating chondral and osteochondral lesions in a group of client-owned dogs with naturally-occurring disease. Records were reviewed for information on signalment, treated joint, underlying pathology (e.g., osteochondritis dissecans; OCD), and type, size, and number of grafts used. Complications were classified as "trivial" if no treatment was provided, "non-surgical" if non-surgical treatment were needed, "minor surgical" if a minor surgical procedure such as pin removal were needed but the graft survived and function was acceptable, or "major" if the graft failed and revision surgery were needed. Outcomes were classified as unacceptable, acceptable, or full function. Thirty-five joints in 33 dogs were treated including nine stifles with lateral femoral condyle (LFC) OCD and 10 stifles with medial femoral condyle (MFC) OCD treated with osteochondral cylinders or "plugs." There were 16 "complex" procedures of the shoulder, elbow, hip, stifle, and tarsus using custom-cut grafts. In total there were eight trivial complications, one non-surgical complication, two minor surgical complications, and five major complications for a total of 16/35 cases with complications. Accordingly, there were five cases with unacceptable outcomes, all of whom had major complications while the other 30 cases had successful outcomes. Of the 30 cases with successful outcomes, 15 had full function and 15 had acceptable function. Based on these subjective outcome assessments, it appears osteochondral allograft transplantation is a viable treatment option in dogs with focal or complex cartilage defects. However, no conclusions can be made regarding the inferiority or superiority of allograft transplantation in comparison to other treatment options based upon these data.