Purpose of Review Trauma is the principle cause of osteoarthritis in the ankle, which is associated with significant morbidity. This review highlights the current literature for the purpose of bringing the reader up-to-date on the management of posttraumatic ankle arthritis, describing treatment efficacy, indications, contraindications, and complications. Recent Findings Recent studies on osteoarthritis have demonstrated variability among anatomic locations regarding the mechanisms and rates of development for posttraumatic osteoarthritis, which are attributed to newly discovered biological differences intrinsic to each joint. Regarding surgical management of posttraumatic ankle arthritis, osteochondral allograft transplantation of the talus, and supramalleolar osteotomies have demonstrated promising results. Additionally, the outpatient setting was found to be appropriate for managing pain following total ankle arthroplasty, associated with low complication rates and no readmission. Summary Management for posttraumatic ankle arthritis is generally progressive. Initial treatment entails nonpharmacologic options with surgery reserved for posttraumatic ankle arthritis refractory to conservative treatment. Patient demographics and lifestyles should be carefully considered when formulating a management strategy, as outcomes are dependent upon the satisfaction of each set of respective criteria. Ultimately, the management of posttraumatic ankle arthritis should be individualized to satisfy the needs and desires, which are specific to each patient.

In this study, we report that human plantar fascia consists of two distinct tissues with differential structural properties. These tissues also contain stem/progenitor cells with differential biological properties. The mechanobiological responses of these two plantar fascia stem cells also differ in terms of expression of collagen I and IV, non-ligament-related genes, and proinflammatory genes. The production of inflammatory agents (prostaglandin E2, interleukin-6) and matrix degradative enzymes (matrix metalloproteinase-1, matrix metalloproteinase-2) are also different between the two types of plantar fascia stem cells. Based on the findings from this study, we suggest that plantar fasciitis results from the aberrant mechanobiological responses of the stem cells from plantar fascia sheath and core tissues. Our findings may also be used to devise tissue engineering approaches to treat plantar fascia injury effectively.

To understand the variable efficacy with platelet rich plasma (PRP) treatments for tendon injury, we determined the differential effects of proteinase-activated receptor (PAR)1- or PAR4-activated PRP (PAR1-PRP, PAR4-PRP) from humans on human patellar tendon stem/progenitor cells (TSCs) and tendon healing. We show that PAR1-PRP released VEGF, whereas PAR4-PRP released endostatin. Treatment of TSCs with PAR1-PRP increased collagen I expression and matrix metalloproteinase-1 (MMP-1), but cells treated with PAR4-PRP increased less collagen I and higher MMP-2 expression. The wound area treated with PAR4-PRP formed tendon-like tissues with well-organized collagen fibers and fewer blood vessels, while PAR1-PRP treatment resulted in the formation of blood vessels and unhealed tissues. These findings indicate that differential activation of PRP leads to different effects on TSCs and tendon healing. We suggest that based on acute or chronic type of tendon injury, selective activation of PRP should be applied in clinics in order to treat injured tendons successfully.

Introduction: Preoperative axillary nerve palsy is a contraindication to reverse total shoulder arthroplasty (rTSA) due to the theoretical risk of higher dislocation rates and poor functional outcomes. Treatment of fracture-dislocations of the proximal humerus with rTSA is particularly challenging, as these injuries commonly present with concomitant neurologic and soft tissue injury. The aim of the current study was to determine the efficacy of rTSA for this fracture pattern in geriatric patients presenting with occult or profound neurologic injury. Methods: A retrospective case series of all shoulder arthroplasty procedures for proximal humerus fractures from February 2006 to February 2018 was performed. Inclusion criteria were patients aged greater than 65 years at the time of surgery, fracture-dislocations of the proximal humerus, and treatment with rTSA. Patients with preoperative nerve injuries were compared to patients without overt neurologic dysfunction. Forward elevation, Quick Disabilities of the Arm, Shoulder, and Hand (QuickDASH), Visual Analog Scale (VAS), and Subjective Shoulder Value (SSV) were obtained at final follow-up. Results: Forty-six rTSA for acute fracture were performed during the study period, 16 patients met the inclusion criteria and 5 (31%) presented with overt preoperative nerve injuries. At mean 3.1 years follow up, there were no postoperative complications including dislocations and final forward elevation was similar between study groups. Patients with overt nerve palsy had higher QuickDASH and VAS scores with lower SSV and self-rated satisfaction. Discussion: In the majority of patients with or without overt nerve injury, rTSA reliably restored overhead function and led to good or excellent patient-rated treatment outcomes. Overt nerve palsy did not lead to higher complication rates, including dislocation. Despite greater disability and less satisfaction, complete or partial nerve recovery can be expected in the majority of patients. Conclusion: Nerve injury following proximal humeral fracture dislocation may not be an absolute contraindication to rTSA.

Objectives:Individuals who participate in sports have an increased risk of osteoarthritis (OA), characterized by articular cartilage degeneration. Currently, there is no cure for OA with treatment aimed at symptom relief and improved function. Muscle-derived stem cells (MDSCs) have been shown to exhibit long-term proliferation, high self-renewal, and multipotent differentiation capabilities in vitro. Previously, we have demonstrated that murine MDSCs retrovirally transduced to express chondrogenic proteins (BMPs) differentiate into chondrocytes and enhance cartilage repair in vivo. Direct injection of therapeutic proteins can promote cartilage healing; however, they have relatively short half-lives requiring muitiple injections of high dosages. This presents a challenge in terms of maintaining adequate local BMP levels and could negatively affect both injured and normal structures and lead to side effects such as osteophyte formation. Gene therapy is a promising approach that addresses this problem; however, its utilization in clinical applications is much further down the road. In order to circumvent viral transduction of cells for cartilage regeneration, we developed a unique growth factor delivery platform comprised of native heparin and a synthetic polycation, poly(ethylene argininylaspartate diglyceride) (PEAD) incorporated with BMP2 (BMP2 coacervate). In this study, we show that sustained delivery of BMP2 via a BMP2 coacervate can induce the differentiation of MDSCs to a chondrocyte lineage for in vivo cartilage regeneration and healing in a Monoiodoacetate (MIA)-induced osteoarthritis model.Methods:mMDSCs were isolated from muscle biopsies via a modified pre-plated technique. The BMP2 coacervates were prepared as previously described. The release profiles of BMP2 coacervate were tested by ELISA. The chondrogenic effects that delivery of BMP2 had on MDSCs were evaluated by RT-PCR. The efficacy of MDSC with BMP2 coacervate were evaluated in vivo in a MIA-induced OA model in C57B6 mice. Mice received an intraarticular injection of 20μl of MIA to induce osteoarthritic lesions. Two weeks after MIA injection, mice were injected with PBS (control), MDSC + free BMP2, or MDSC + BMP2 coacervate. Histologic evaluations of cartilage regeneration were conducted at week 4. Institutional Animal Care and Use Committee approval was obtained prior to all animal studies.Results:Release profiles of BMP2 showed sustained release for more than 28 days demonstrating sustained release. The chondrogenic differentiation of MDSCs following BMP2 delivery was assayed using cell culture. The mRNA expression of Aggrecan and Col2A were significantly higher in each BMP2 group compared to control or vehicle only (P<0.05). Multi-dosage free BMP2 demonstrated significantly higher Aggrecan expression compared to single dose free BMP2 (p<0.05). Col2A and aggrecan expression in the BMP coacervate group was superior to both single and mult-dose free BMP2 delivery (p<0.05) (Fig 1A). Histologic examination demonstrated superior cartilage repair an...

Category: Basic Sciences/Biologics Introduction/Purpose: Tendon injuries occur frequently and cost billions of health care dollars annually. Recently, there has been an increase in the use of platelet-rich plasma (PRP) to treat tendon injuries. However, the efficacy of PRP treatment is controversial due to inconsistent results from human clinical trials. It is thought that variations in PRP preparation contribute to these inconsistencies. Specifically, platelets in PRP contain pro-angiogenic (e.g. VEGF) or anti-angiogenic (e.g. endostatin) factors, which may differentially affect the healing of tendon injuries. It is known that these factors are selectively released after platelet activation by specific receptors. Therefore, in this study we investigated the effect of protease-activated receptors 1 and 4 (PAR1 and PAR4) in platelet activation and inflammation. Methods: Platelet preparation – Human blood was obtained from 12 healthy donors and 9 ml of blood was mixed with 1 ml of 3.8% sodium citrate and centrifuged at 500g for 10 min. Then, the supernatant (PRP) without the buffy coat was centrifuged at 1000g for 10 min and the resulting pellet was washed in Tyrodes-HEPES buffer and centrifuged for 10 min at 1000g. Finally, platelets in the pellet was suspended in Tyrodes-HEPES buffer and used in experiments. Platelet activation – About 100 μl of platelet from above was activated with 5 μl 1 mM PAR1-activating peptide (PAR1-AP) or PAR4-activating peptide (PAR4-AP) at 25°C for 10 min. Then, the mixture was centrifuged at 1000g for 10 min, and the levels of VEGF, endostatin, IL-1RA and HMGB-1in the supernatant was determined by ELISA. Platelets without activators were used as controls. Results: PAR1 induced angiogenic effects in human platelets. PAR1 activated platelets released 3 times more VEGF than when activated with PAR4 (Fig. 1A). However, PAR4 activated platelets released 7 times more endostatin than the PAR1 activated platelets (Fig. 1B). Further, PAR1 induced anti-inflammatory effects in human platelets; it did not change IL-1R-A (Fig. 2A) but decreased HMGB-1 levels (Fig. 2B). In contrast, PAR4 stimulated inflammatory effects in human platelets by lowering IL-1-RA and increasing HMGB-1 levels. Conclusion: Our findings indicate that PAR1 induces angiogenetic and anti-inflammatory effects in human platelets, while PAR4 has anti-angiogenetic and inflammatory effects. Of significance is HMGB-1, which is constitutively expressed in the nuclei of most mammalian cells. Under cellular stress, HMGB1 is released into the extracellular matrix and activates the immune response thus acting as a danger-signal. Both PAR1 and PAR4 selectively regulated the release of VEGF and endostatin, and IL-1RA and HMGB-1 from human platelets. Therefore, the role of PAR1 and PAR4 on human platelet activation and inflammation should be considered prior to the use of PRP to treat tendon injuries.

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O plasma rico em plaquetas (PRP) é um hemocomponente produzindo a partir do plasma, visando a obtenção de citocinas e fatores do crescimento com fins terapêuticos, como a cicatrização e reparação de diferentes tecidos. Esse estudo quantificou a concentração plaquetária obtida utilizando-se de três diferentes protocolos de obtenção do PRP de 13 amostras de sangue de 7 cães hígidos. As velocidades de centrifugação utilizadas no protocolo I foram de 1ª centrifugação de 1.500 rpm e 2ª centrifugação de 3.000 rpm; no protocolo II, de 2.000 rpm e 3.000 rpm; e o protocolo III com 3.000 rpm e 4.000 rpm, respectivamente. O melhor resultado para a produção de PRP autólogo foi obtido no protocolo 1, seguido do protocolo 2, com aumentos de 116% e 83,05% após a 2ª centrifugação, respectivamente. Entretanto, os resultados obtidos na 1ª centrifugação foram superiores aos apresentados após a 2ª. centrifugação, observando elevações de 203,66% e 210,20% comparados aos valores basais.