Nonoperative and Operative Soft-Tissue, Cartilage, and Bony Regeneration and Orthopaedic Biologics of the Elbow and Upper Extremity: An Orthoregeneration Network Foundation Review.

Orthoregeneration is defined as a solution for orthopaedic conditions that harnesses the benefits of biology to improve healing, reduce pain, improve function, and, optimally, provide an environment for tissue regeneration. Options include drugs, surgical intervention, scaffolds, biologics as a product of cells, and physical and electromagnetic stimuli. The goal of regenerative medicine is to enhance the healing of tissue after musculoskeletal injuries as both isolated treatment and adjunct to surgical management, using novel therapies to improve recovery and outcomes. Various orthopaedic biologics (orthobiologics) have been investigated for the treatment of pathology involving the elbow and upper extremity, including the tendons (lateral epicondylitis, medial epicondylitis, biceps tendonitis, triceps tendonitis), articular cartilage (osteoarthritis, osteochondral lesions), and bone (fractures, nonunions, avascular necrosis, osteonecrosis). Promising and established treatment modalities include hyaluronic acid; botulinum toxin; corticosteroids; leukocyte-rich and leukocyte-poor platelet-rich plasma; autologous blood; bone marrow aspirate comprising mesenchymal stromal cells (alternatively termed medicinal signaling cells and frequently mesenchymal stem cells [MSCs]) and bone marrow aspirate concentrate; MSCs harvested from adipose and skin (dermis) sources; vascularized bone grafts; bone morphogenic protein scaffold made from osteoinductive and conductive ß-tricalcium phosphate and poly-ε-caprolactone with hydrogels, human MSCs, and matrix metalloproteinases; and collagen sponge. Autologous blood preparations such as autologous blood injections and platelet-rich plasma show positive outcomes for nonresponsive tendinopathy. In addition, cellular therapies such as tissue-derived tenocyte-like cells and MSCs show a promising ability to regulate degenerative processes by modulating tissue response to inflammation and preventing continuous degradation and support tissue restoration.

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.

Fibroblasts From Common Anterior Cruciate Ligament Tendon Grafts Exhibit Different Biologic Responses to Mechanical Strain.

BACKGROUND: Different tendons are chosen for anterior cruciate ligament (ACL) reconstruction based on perceived advantages and disadvantages, yet there is a relative paucity of information regarding biologic responsiveness of commonly used tendon grafts to mechanical strain. PURPOSE: To evaluate the in vitro responses of graft fibroblasts derived from tendons used for ACL reconstruction to clinically relevant strain levels. STUDY DESIGN: Controlled laboratory study. METHODS: Twelve quadriceps tendons (QTs), 12 patellar tendons (PTs), and 9 hamstring tendons (HTs) were harvested from skeletally mature dogs (n = 16). Tendon fibroblasts were isolated and seeded onto BioFlex plates (1 × 105 cells/well). Cells were subjected to 3 strain conditions (stress deprivation, 0%; physiologic, 4%; high, 10%) for 5 days. Media were collected for proinflammatory and metabolic assays. RNA was extracted for gene expression analysis using real-time reverse transcription polymerase chain reaction. RESULTS: Stress deprivation elicited significantly higher metabolic activity from HT and PT cells than from QT cells (P < .001 and P = .001, respectively). There were no differences in metabolic activity among all 3 graft fibroblasts at physiologic and high strain. COL-1 expression was significantly higher in PT versus HT during physiologic strain (P = .007). No significant differences with COL-3 expression were seen. TIMP-1 (P = .01) expression was higher in PT versus HT under physiologic strain. Scleraxis expression was higher in PT versus HT (P = .007) under physiologic strain. A strain-dependent increase in PGE2 levels occurred for all grafts. At physiologic strain conditions, HT produced significantly higher levels of PGE2 versus QT (P < .001) and PT (P = .005). CONCLUSION: Fibroblasts from common ACL graft tissues exhibited different metabolic responses to mechanical strain. On the basis of these data, we conclude that early production of extracellular matrix and proinflammatory responses from ACL grafts are dependent on mechanical loading and graft source. CLINICAL RELEVANCE: Graft-specific differences in ACL reconstruction outcomes are known to exist. Our results suggest that there are differences in the biologic responsiveness of cells from the tendon grafts used in ACL reconstruction, which are dependent on strain levels and graft source. The biologic properties of the tissue used for ACL reconstruction should be considered when selecting graft source.

The differentiating ability of four plasma biomarkers in canine hip dysplasia.

BACKGROUND: The accumulation of cartilage breakdown products in body fluids has been extensively investigated to assess the accuracy of molecular biomarkers from a diagnostic, prognostic, and therapeutic perspective. Nevertheless, to the authors' knowledge, there is a lack of information about spontaneous models of hip osteoarthritis and the differentiating ability of collagen, noncollagen, and inflammatory biomarkers. OBJECTIVES: We aimed to assess the accuracy of four plasma biomarkers that could differentiate between healthy dogs and dogs with hip dysplasia. METHODS: Twenty-four dogs were used in this institutionally approved study (12 in the mild to severe hip dysplasia group; 12 in the control group). Plasma concentrations of biomarkers were compared. The ability of each marker to differentiate control from diseased dogs was assessed using an independent t-test, logistic regression, and receiving operating characteristics (ROC) analysis. RESULTS: Three biomarkers were significantly different between the two groups. The collagen marker procollagen type II propeptide (PIICP) was useful in differentiating between control and diseased dogs with the best combination of sensitivity and specificity. The four biomarkers showed high area under the curve (AUC) values. CONCLUSIONS: The results indicate that plasma biomarkers can be used as a screening tool for canine hip dysplasia. Although the cutoff values and diagnostic ability of the biomarkers used in this study show promising results, the sources of individual variability should be addressed. Future studies with larger groups of dogs are needed to correlate plasma levels in serum and synovial fluid during clinical disease.