Morrey, Mark E.

ABSTRACTDegenerative disk disease of the spine is a major cause of back pain and disability. Optimization of regenerative medical therapies for degenerative disk disease requires a deep mechanistic understanding of the factors controlling the structural integrity of spinal tissues. In this investigation, we sought to identify candidate regulatory genes controlling extracellular matrix synthesis in spinal tissues. To achieve this goal we performed high throughput next generation RNA sequencing on 39 annulus fibrosus and 21 nucleus pulposus human tissue samples. Specimens were collected from patients undergoing surgical discectomy for the treatment of degenerative disk disease. Our studies identified associations between extracellular matrix genes, growth factors, and other important regulatory molecules. The fibrous matrix characteristic of annulus fibrosus was associated with expression of the growth factors platelet derived growth factor beta (PDGFB), vascular endothelial growth factor C (VEGFC), and fibroblast growth factor 9 (FGF9). Additionally we observed high expression of multiple signaling proteins involved in the NOTCH and WNT signaling cascades. Nucleus pulposus extracellular matrix related genes were associated with the expression of numerous diffusible growth factors largely associated with the transforming growth signaling cascade, including transforming factor alpha (TGFA), inhibin alpha (INHA), inhibin beta A (INHBA), bone morphogenetic proteins (BMP2, BMP6), and others. Clinical significance: this investigation provides important data on extracellular matrix gene regulatory networks in disk tissues. This information can be used to optimize pharmacologic, stem cell, and tissue engineering strategies for regeneration of the intervertebral disk and the treatment of back pain. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1356–1369, 2018.

Cellular therapies, such as stem cell–based treatments, have been widely researched and numerous products and treatments have been developed. Despite this, there has been relatively limited use of these technologies in the healthcare sector. This study sought to investigate the perceived barriers to this more widespread adoption. An anonymous online questionnaire was developed, based on the findings of a pilot study. This was distributed to an audience of clinicians, researchers and commercial experts in 13 countries. The results were analysed for all respondents, and also sub-grouped by geographical region, and by profession of respondents. The results of the study showed that the most significant barrier was manufacturing, with other factors such as efficacy, regulation and cost-effectiveness being identified by the different groups. This study further demonstrates the need for these important issues to be addressed during the development of cellular therapies to enable more widespread adoption of these treatments.

AbstractSubstance P (SP), a neurotransmitter released after injury, has been linked to deregulated tissue repair and fibrosis in musculoskeletal tissues and other organs. Although SP inhibition is an effective treatment for nausea, it has not been previously considered as an anti‐fibrotic therapy. Although there are extensive medical records of individuals who have used SP antagonists, our analysis of human registry data revealed that patients receiving these antagonists and arthroplasty are exceedingly rare, thus precluding a clinical evaluation of their potential effects in the context of arthrofibrosis. Therefore, we pursued in vivo studies to assess the effect of SP inhibition early after injury on pro‐fibrotic gene expression and contractures in an animal model of post‐traumatic joint stiffening. Skeletally mature rabbits (n = 24) underwent surgically induced severe joint contracture, while injected with either fosaprepitant (a selective SP antagonist) or saline (control) early after surgery (3, 6, 12, and 24 h). Biomechanical testing revealed that differences in mean contracture angles between the groups were not statistically significant (P = 0.27), suggesting that the drug neither mitigates nor exacerbates joint contracture. However, microarray gene expression analysis revealed that mRNA levels for proteins related to cell signaling, pro‐angiogenic, pro‐inflammatory, and collagen matrix production were significantly different between control and fosaprepitant treated rabbits (P < 0.05). Hence, our study demonstrates that inhibition of SP alters expression of pro‐fibrotic genes in vivo. This finding will motivate future studies to optimize interventions that target SP to reduce the formation of post‐traumatic joint contractures.

Background The purpose of the present study was to determine the cost of two-stage reimplantation for the treatment of deep infection after total elbow arthroplasty (TEA) and compare this with primary and aseptic revision TEA. Methods Three hundred and seventy-one primary TEA and 286 revision TEAs (including 47 elbows requiring two-stage reimplantation) were performed. Total direct medical costs during each hospitalization were obtained from our institutional research database and compared for three groups: primary TEA, revision for nonseptic reasons and two-stage reimplantation for deep infection. Results The mean cost of an uncomplicated primary TEA and aseptic revision TEA was $18,464 and $18,796, respectively. The mean overall cost associated with two-stage reimplantation increased to $34,286. Two-stage reimplantation increased both Part A (hospital costs) and Part B (professional costs). The mean Part A cost for septic revision TEA was $29,102 versus $15,844 for primary TEA. The mean Part B cost for septic revision TEA was $5,184 versus $2,621 for primary TEA. Conclusions Two-stage reimplantation for treatment of an infected TEA costs 186% the hospital cost of a primary uncomplicated or aseptic revision TEA. The overall cost to society is even greater if we take into account the cost of antibiotic therapy in between stages and lost days from work.

Objectives Sustained intra-articular delivery of pharmacological agents is an attractive modality but requires use of a safe carrier that would not induce cartilage damage or fibrosis. Collagen scaffolds are widely available and could be used intra-articularly, but no investigation has looked at the safety of collagen scaffolds within synovial joints. The aim of this study was to determine the safety of collagen scaffold implantation in a validated in vivo animal model of knee arthrofibrosis. Materials and Methods A total of 96 rabbits were randomly and equally assigned to four different groups: arthrotomy alone; arthrotomy and collagen scaffold placement; contracture surgery; and contracture surgery and collagen scaffold placement. Animals were killed in equal numbers at 72 hours, two weeks, eight weeks, and 24 weeks. Joint contracture was measured, and cartilage and synovial samples underwent histological analysis. Results Animals that underwent arthrotomy had equivalent joint contractures regardless of scaffold implantation (-13.9° versus -10.9°, equivalence limit 15°). Animals that underwent surgery to induce contracture did not demonstrate equivalent joint contractures with (41.8°) or without (53.9°) collagen scaffold implantation. Chondral damage occurred in similar rates with (11 of 48) and without (nine of 48) scaffold implantation. No significant difference in synovitis was noted between groups. Absorption of the collagen scaffold occurred within eight weeks in all animals Conclusion Our data suggest that intra-articular implantation of a collagen sponge does not induce synovitis or cartilage damage. Implantation in a native joint does not seem to induce contracture. Implantation of the collagen sponge in a rabbit knee model of contracture may decrease the severity of the contracture. Cite this article: J. A. Walker, T. J. Ewald, E. Lewallen, A. Van Wijnen, A. D. Hanssen, B. F. Morrey, M. E. Morrey, M. P. Abdel, J. Sanchez-Sotelo. Intra-articular implantation of collagen scaffold carriers is safe in both native and arthrofibrotic rabbit knee joints. Bone Joint Res 2016;6:162–171. DOI: 10.1302/2046-3758.63.BJR-2016-0193.

AimsWe describe the use of a protocol of irrigation and debridement (I& D) with retention of the implant for the treatment of periprosthetic infection of a total elbow arthroplasty (TEA). This may be an attractive alternative to staged re-implantation.Patients and MethodsBetween 1990 and 2010, 23 consecutive patients were treated in this way. Three were lost to follow-up leaving 20 patients (21 TEAs) in the study. There were six men and 14 women. Their mean age was 58 years (23 to 76). The protocol involved: component unlinking, irrigation and debridement (I& D), and the introduction of antibiotic laden cement beads; organism-specific intravenous antibiotics; repeat I& D and re-linkage of the implant if appropriate; long-term oral antibiotic therapy.ResultsThe mean follow-up was 7.1 years (2 to 16). The infecting micro-organisms were Staphylococcus aureus in nine, coagulase-negative Staphylococcus in 13, Corynebacterium in three and other in six cases. Re-operations included three repeat staged I& Ds, two repeat superficial I& Ds and one fasciocutaneous forearm flap. One patient required removal of the implant due to persistent infection. All except three patients rated their pain as absent or mild. Outcome was rated as good or excellent in 15 patients (mean Mayo Elbow Performance Score 78 points, (5 to 100) with a mean flexion-extension arc of 103° (40° to 150°)).ConclusionA staged protocol can be successful in retaining stable components of an infected TEA. Function of the elbow may compare unfavourably to that after an uncomplicated TEA. Cite this article: Bone Joint J 2016;98-B:976–83.

Abstract There are three main patterns of complex elbow instability: posterolateral (terrible triad), varus posteromedial (anteromedial coronoid fracture with lateral collateral ligament complex disruption), and trans-olecranon fracture dislocations. Radial head fractures, in the setting of complex elbow instability, often require internal fixation or arthroplasty; the outcome of radial head replacement is dictated by adequate selection of the head diameter, correct restoration of radial length, and proper alignment and tracking. Small coronoid fractures can be ignored. Larger coronoid fractures, especially those involving the anteromedial facet, require fixation or graft reconstruction, particularly in the presence of incongruity. The lateral collateral ligament complex should be repaired whenever disrupted. Medial collateral ligament disruptions seem to heal reliably without surgical repair provided all other involved structures are addressed. The most common mistakes in the management of trans-olecranon fracture dislocations are suboptimal fixation, lack of fixation of coronoid fragments, and lack of restoration of the natural dorsal angulation of the ulna. Cite this article: Sanchez-Sotelo J, Morrey M. Complex elbow instability. EFORT Open Rev 2016;1:183-190.

Aims Animal models have been developed that allow simulation of post-traumatic joint contracture. One such model involves contracture-forming surgery followed by surgical capsular release. This model allows testing of antifibrotic agents, such as rosiglitazone. Methods A total of 20 rabbits underwent contracture-forming surgery. Eight weeks later, the animals underwent a surgical capsular release. Ten animals received rosiglitazone (intramuscular initially, then orally). The animals were sacrificed following 16 weeks of free cage mobilisation. The joints were tested biomechanically, and the posterior capsule was assessed histologically and via genetic microarray analysis. Results There was no significant difference in post-traumatic contracture between the rosiglitazone and control groups (33° (standard deviation (sd) 11) vs 37° (sd14), respectively; p = 0.4). There was no difference in number or percentage of myofibroblasts. Importantly, there were ten genes and 17 pathways that were significantly modulated by rosiglitazone in the posterior capsule. Discussion Rosiglitazone significantly altered the genetic expression of the posterior capsular tissue in a rabbit model, with ten genes and 17 pathways demonstrating significant modulation. However, there was no significant effect on biomechanical or histological properties. Cite this article: M. P. Abdel. Effectiveness of rosiglitazone in reducing flexion contracture in a rabbit model of arthrofibrosis with surgical capsular release: A biomechanical, histological, and genetic analysis. Bone Joint Res 2016;5:11–17. doi: 10.1302/2046-3758.51.2000593

There has been a large increase in basic science activity in cell therapy and a growing portfolio of cell therapy trials. However, the number of industry products available for widespread clinical use does not match this magnitude of activity. We hypothesize that the paucity of engagement with the clinical community is a key contributor to the lack of commercially successful cell therapy products. To investigate this, we launched a pilot study to survey clinicians from five specialities and to determine what they believe to be the most significant barriers to cellular therapy clinical development and adoption. Our study shows that the main concerns among this group are cost-effectiveness, efficacy, reimbursement, and regulation. Addressing these concerns can best be achieved by ensuring that future clinical trials are conducted to adequately answer the questions of both regulators and the broader clinical community.