Direct 3D printing of decellularized matrix embedded composite polycaprolactone scaffolds for cartilage regeneration.

Treatment options for large osteochondral injuries (OCIs) are limited by donor tissue scarcity, morbidity, and anatomic mismatch. 3D printing technology can produce patient-specific scaffolds to address these large defects. Thermoplastics like polycaprolactone (PCL) offer necessary mechanical properties, but lack bioactivity. We fabricated 3D printed PCL scaffolds embedded with polylactic acid microspheres containing decellularized cartilage matrix (DM). DM incorporation within polylactic acid microspheres prevented its thermal degradation during the 3D printing process. The scaffolds replicated the mechanical properties of native cartilage and demonstrated controlled release of DM proteins. Human mesenchymal stem cells (hMSCs) seeded on the composite scaffolds with DM and cultured in basal media self-assembled into aggregates mimicking mesenchymal condensates during embryonic development. The DM composite scaffolds also induced higher expression of biochemical markers of cartilage development than controls, providing evidence for their translational application in the treatment of OCIs. The present study demonstrates the potential of direct incorporation of DM with thermoplastics for 3D printing of patient-specific scaffolds for osteochondral regeneration.

Pediatric and Adolescent Fractures of the Acetabulum Treated With ORIF: What Are Their Functional Outcomes?

OBJECTIVES: To evaluate the functional outcomes of pediatric and adolescent patients (<18 year old) who sustained acetabulum fractures that were treated with open reduction internal fixation (ORIF). DESIGN: Retrospective cohort. SETTING: Level 1 trauma center. PATIENTS: Thirty-four pediatric and adolescent patients underwent acetabulum fracture ORIF between 2001 and 2018. Of the operatively treated patients, 21 patients had sufficient follow-up (>6 months), one died after fixation secondary to other traumatic injuries, and 12 patients were lost to follow-up. INTERVENTION: Acetabulum fracture ORIF. MAIN OUTCOME MEASUREMENT: The SF-36 Health Survey and Short Musculoskeletal Functional Assessment (SMFA) were compared with population norms. The modified Merle d'Aubigné clinical hip score, Matta radiologic outcome, and postoperative complications were also documented. RESULTS: Functional outcome data were available at a mean of 5 years 2 months. Mean SF-36 scores were 44.8 and 50.1 for the physical component score and mental component scores, respectively, which did not differ significantly from US population norms (physical component score mean: 50, P = 0.061 and mental component score mean: 50, P = 0.973). Furthermore, the mean SMFA Bother Index score was 18.6, which is not significantly different from the population norm mean of 13.8 (P = 0.268). However, the function index mean was 31.9, which was significantly worse than the population norm mean of 12.7 (P = 0.001). Two patients with a delayed reduction (>6 hours) of an acetabulum fracture dislocation had poor outcomes related to the development of avascular necrosis and post-traumatic osteoarthritis. CONCLUSION: In this small cohort, 86% (18/21) of these patients had a favorable functional outcome with the exception of the SMFA Functional Index that was significantly less than population norms. Although long-term follow-up is needed, we advocate for operative management of pediatric and adolescent acetabulum fractures when adult displacement and instability criteria are present. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Tissue Engineering Strategies for Treating Avascular Necrosis of the Femoral Head.

Avascular necrosis (AVN) of the femoral head commonly leads to symptomatic osteoarthritis of the hip. In older patients, hip replacement is a viable option that restores the hip biomechanics and improves pain but in pediatric, adolescent, and young adult patients hip replacements impose significant activity limitations and the need for multiple revision surgeries with increasing risk of complication. Early detection of AVN requires a high level of suspicion as diagnostic techniques such as X-rays are not sensitive in the early stages of the disease. There are multiple etiologies that can lead to this disease. In the pediatric and adolescent population, trauma is a commonly recognized cause of AVN. The understanding of the pathophysiology of the disease is limited, adding to the challenge of devising a clinically effective treatment strategy. Surgical techniques to prevent progression of the disease and avoid total hip replacement include core decompression, vascular grafts, and use of bone-marrow derived stem cells with or without adjuncts, such as bisphosphonates and bone morphogenetic protein (BMP), all of which are partially effective only in the very early stages of the disease. Further, these strategies often only improve pain and range of motion in the short-term in some patients and do not predictably prevent progression of the disease. Tissue engineering strategies with the combined use of biomaterials, stem cells and growth factors offer a potential strategy to avoid metallic implants and surgery. Structural, bioactive biomaterial platforms could help in stabilizing the femoral head while inducing osteogenic differentiation to regenerate bone and provide angiogenic cues to concomitantly recover vasculature in the femoral head. Moreover, injectable systems that can be delivered using a minimal invasive procedure and provide mechanical support the collapsing femoral head could potentially alleviate the need for surgical interventions in the future. The present review describes the limitations of existing surgical methods and the recent advances in tissue engineering that are leading in the direction of a clinically effective, translational solution for AVN in future.

Fibrinogen activates focal adhesion kinase (FAK) promoting colorectal adenocarcinoma growth.

BACKGROUND: We previously showed that fibrinogen is a major determinant of the growth of a murine model of colorectal cancer (CRC). OBJECTIVE: Our aim was to define the mechanisms coupling fibrin(ogen) to CRC growth. RESULTS: CRC tumors transplanted into the dorsal subcutis of Fib- mice were less proliferative and demonstrated increased senescence relative to those grown in Fib+ mice. RNA-seq analyses of Fib+ and Fib- tumors revealed 213 differentially regulated genes. One gene highly upregulated in tumors from Fib- mice was stratifin, encoding 14-3-3σ, a master regulator of proliferation/senescence. In a separate cohort, we observed significantly increased protein levels of 14-3-3σ and its upstream and downstream targets (i.e., p53 and p21) in tumors from Fib- mice. In vitro analyses demonstrated increased tumor cell proliferation in a fibrin printed three-dimensional environment compared with controls, suggesting that fibrin(ogen) in the tumor microenvironment promotes tumor growth in this context via a tumor cell intrinsic mechanism. In vivo analyses showed diminished activation of focal adhesion kinase (FAK), a key negative regulator of p53, in Fib- tumors. Furthermore, nuclear magnetic resonance-based metabolomics demonstrated significantly reduced metabolic activity in tumors from Fib- relative to Fib+ mice. Together, these findings suggest that fibrin(ogen)-mediated engagement of colon cancer cells activates FAK, which inhibits p53 and its downstream targets including 14-3-3σ and p21, thereby promoting cellular proliferation and preventing senescence. CONCLUSIONS: These studies suggest that fibrin(ogen) is an important component of the colon cancer microenvironment and may be exploited as a potential therapeutic target.

Obesity as a Predictor of Outcomes in Type III and Type IV Supracondylar Humerus Fractures.

OBJECTIVES: To investigate the association of obesity with fracture characteristics and outcomes of operatively treated pediatric supracondylar humerus fractures. DESIGN: Retrospective multicenter. SETTING: Two Level I pediatric hospitals. PATIENTS: Patients (age <18 years) with operatively treated Gartland type III and type IV fractures 2010-2014. INTERVENTION: Closed or open reduction and percutaneous pinning of supracondylar humerus fractures. MAIN OUTCOME MEASURE: Incidence of Gartland IV fracture, preoperative nerve palsy, open reduction and complication rates. RESULTS: Patients in the obese group had a significantly higher likelihood of having a Gartland IV fracture (not obese: 17%; obese: 35%; P = 0.007). There was a significantly higher incidence of nerve palsy on presentation in the obese group (not obese: 20%; obese: 33%; P = 0.03). No significant differences were found between groups regarding incidence of open reduction, compartment syndrome, and rates of reoperation. CONCLUSIONS: The present study demonstrates that obese children with a completely displaced supracondylar humerus fractures have an increased risk of Gartland type IV and preoperative nerve palsy compared with normal weight children. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

The corona mortis: is it a rare and dangerous anomaly in adolescents undergoing periacteabular osteotomy?

The corona mortis (CM) is a vascular connection between the obturator and external iliac or internal epigastric vessels that has historically been identified as a source of hemorrhage in pelvic surgery. However, its frequency, location, proximity to the osteotomies performed, vascular contributions and impact on blood loss in patients undergoing periacetabular osteotomy (PAO) are unknown. We sought to identify the frequency, origin, location relative to osteotomies performed during surgery and impact on blood loss of the CM. Preoperative magnetic resonance imaging (MRI) of the hips of 28 adolescent patients (56 hips) undergoing PAO was retrospectively reviewed for the presence of a CM. When identifiable, the size, nature (arterial or venous), orientation, position relative to the iliopectineal eminence (IPE) and associated estimated blood loss (EBL) were recorded. 75% (21/28) of patients possessed an identifiable, ipsilateral CM to the site of PAO, 90% of which were venous and 10% arterial. The vessel was typically 8.3 ± 3.8 mm medial and 11.1 ± 5.3 mm caudal from the anterosuperomedial edge of the IPE. There was no significant difference in the amount of EBL (519 ± 260 versus 694 ± 369 ml) or need for post-op transfusions (1/21 versus 0/7) between patients who possessed a CM and those who did not, respectively (P = 0.21). CM was more prevalent in this study than previously reported. However, the presence of an ipsilateral CM was not associated with an increase in EBL or transfusion during routine PAO surgery using modern surgical techniques.

Bone xenotransplantation: A review of the history, orthopedic clinical literature, and a single-center case series.

BACKGROUND: One-half of all orthopedic surgeries require bone grafting for successful outcomes in fusions, reconstructive procedures, and the treatment of osseous defects resulting from trauma, tumor, infection, or congenital deformity. Autologous bone grafts are taken from the patient's own body and remain the "gold standard" graft choice but are limited in supply and impart significant patient morbidity. Xenograft bone is an attractive alternative from donors with controlled biology, in large supply and at a theoretically lower cost. Clinical results with xenograft bone for orthopedic applications have been mixed in the limited clinical trials published. METHODS: In the current review, we introduce fundamental principles of bone grafting, systematically review all orthopedic clinical studies reporting outcomes on patients transplanted with xenograft bone, and we present our own clinical results from patients grafted with bovine bone in foot and ankle reconstructive procedures. RESULTS: Thirty-one clinical studies were identified for review and the majority (47%) were from spine surgery literature. Favorable results were reported in 44% of studies while 47% of studies reported poor outcomes and discouraged use of xenograft bone products. In our own clinical series, xenograft failed to integrate with host bone in 58% of cases and persistent pain was reported in 83% of cases. CONCLUSIONS: This is the first systematic review of clinical results reported after bone xenotransplantation for orthopaedic surgery applications. Current literature does not support the use of xenograft bone products and our institution's results are consistent with this conclusion. Our laboratory has reported promising pre-clinical results with a xenograft product derived from porcine cancellous bone, but additional testing is required before considering clinical translation.

Investigating the Osteoinductive Potential of a Decellularized Xenograft Bone Substitute.

Bone grafting is the second most common tissue transplantation procedure worldwide. One of the alternative methods for bone repair under investigation is a tissue-engineered bone substitute. An ideal property of tissue-engineered bone substitutes is osteoinductivity, defined as the ability to stimulate primitive cells to differentiate into a bone-forming lineage. In the current study, we use a decellularization and oxidation protocol to produce a porcine bone scaffold and examine whether it possesses osteoinductive potential and can be used to create a tissue-engineered bone microenvironment. The decellularization protocol was patented by our lab and consists of chemical decellularization and oxidation steps using combinations of deionized water, trypsin, antimicrobials, peracetic acid, and triton-X100. To test if the bone scaffold was a viable host, preosteoblasts were seeded and analyzed for markers of osteogenic differentiation. The osteoinductive potential was observed in vitro with similar osteogenic markers being expressed in preosteoblasts seeded on the scaffolds and demineralized bone matrix. To assess these properties in vivo, scaffolds with and without preosteoblasts preseeded were subcutaneously implanted in mice for 4 weeks. MicroCT scanning revealed 1.6-fold increased bone volume to total volume ratio and 1.4-fold increase in trabecular thickness in scaffolds after implantation. The histological analysis demonstrates new bone formation and blood vessel formation with pentachrome staining demonstrating osteogenesis and angiogenesis, respectively, within the scaffold. Furthermore, CD31+ staining confirmed the endothelial lining of the blood vessels. These results demonstrate that porcine bone maintains its osteoinductive properties after the application of a patented decellularization and oxidation protocol developed in our laboratory. Future work must be performed to definitively prove osteogenesis of human mesenchymal stem cells, biocompatibility in large animal models, and osteoinduction/osseointegration in a relevant clinical model in vivo. The ability to create a functional bone microenvironment using decellularized xenografts will impact regenerative medicine, orthopedic reconstruction, and could be used in the research of multiple diseases.

A porcine xenograft-derived bone scaffold is a biocompatible bone graft substitute: An assessment of cytocompatibility and the alpha-Gal epitope.

BACKGROUND: Xenografts are an attractive alternative to traditional bone grafts because of the large supply from donors with predictable morphology and biology as well as minimal risk of human disease transmission. Clinical series involving xenograft bone transplantation, most commonly from bovine sources, have reported poor results with frequent graft rejection and failure to integrate with host tissue. Failures have been attributed to residual alpha-Gal epitope in the xenograft which humans produce natural antibody against. To the authors' knowledge, there is currently no xenograft-derived bone graft substitute that has been adopted by orthopedic surgeons for routine clinical use. METHODS: In the current study, a bone scaffold intended to serve as a bone graft substitute was derived from porcine cancellous bone using a tissue decellularization and chemical oxidation protocol. In vitro cytocompatibility, pathogen clearance, and alpha-Gal quantification tests were used to assess the safety of the bone scaffold intended for human use. RESULTS: In vitro studies showed the scaffold was free of processing chemicals and biocompatible with mouse and human cell lines. When bacterial and viral pathogens were purposefully added to porcine donor tissue, processing successfully removed these pathogens to comply with sterility assurance levels established by allograft tissue providers. Critically, 98.5% of the alpha-Gal epitope was removed from donor tissue after decellularization as shown by ELISA inhibition assay and immunohistochemical staining. CONCLUSIONS: The current investigation supports the biologic safety of bone scaffolds derived from porcine donors using a decellularization protocol that meets current sterility assurance standards. The majority of the highly immunogenic xenograft carbohydrate was removed from donor tissue, and these findings support further in vivo investigation of xenograft-derived bone tissue for orthopedic clinical application.

A Dedicated Fracture Reduction Room: A Cost-Effective Alternative to the Operating Room.

INTRODUCTION: Charges, procedural efficiency, return to activity, and complications after closed treatment of fractures performed in an operating room (OR) versus closed reduction in a dedicated fracture reduction room (FRR) were compared. METHODS: Patients with closed fractures of the forearm who underwent closed reduction in the year before (OR), and after implementation of the FRR, were retrospectively reviewed. Charges, American Society of Anesthesiologists class, sex, age, length of follow-up, prior reduction, fracture location/displacement, time from injury to procedure, procedural time, time to return to activity, and complications were recorded. RESULTS: Eighteen patients met the inclusion criteria in the FRR group (13 men, 5 women), and 22 in the OR group (18 men, 4 women). No notable differences in age, sex, follow-up, American Society of Anesthesiologists class, fracture location/displacement, incidence of prior reduction, or time to return to activity were observed. Two (9.5%) complications occurred in the FRR group versus 7 (32%) in the OR group, P > 0.05. No anesthesia complications were present. Patients treated in the FRR incurred charges of $5,299 ± $1,289 versus $10,455 ± $2,290 in the OR, P < 0.001. Total time of visit in the FRR was ∼30% less than the OR, P < 0.001. No notable delay in treatment was observed. DISCUSSION: In the era of finite resources and value-based care, implementation of a FRR resulted in safe, cost-effective, and increased procedural efficiency.

Novel Process for 3D Printing Decellularized Matrices.

3D bioprinting aims to create custom scaffolds that are biologically active and accommodate the desired size and geometry. A thermoplastic backbone can provide mechanical stability similar to native tissue while biologic agents offer compositional cues to progenitor cells, leading to their migration, proliferation, and differentiation to reconstitute the original tissues/organs1 , 2. Unfortunately, many 3D printing compatible, bioresorbable polymers (such as polylactic acid, PLA) are printed at temperatures of 210 °C or higher - temperatures that are detrimental to biologics. On the other hand, polycaprolactone (PCL), a different type of polyester, is a bioresorbable, 3D printable material that has a gentler printing temperature of 65 °C. Therefore, it was hypothesized that decellularized extracellular matrix (DM) contained within a thermally protective PLA barrier could be printed within PCL filament and remain in its functional conformation. In this work, osteochondral repair was the application for which the hypothesis was tested. As such, porcine cartilage was decellularized and encapsulated in polylactic acid (PLA) microspheres which were then extruded with polycaprolactone (PCL) into filament to produce 3D constructs via fused deposition modeling. The constructs with or without the microspheres (PLA-DM/PCL and PCL(-), respectively) were evaluated for differences in surface features.

A Decellularized Porcine Xenograft-Derived Bone Scaffold for Clinical Use as a Bone Graft Substitute: A Critical Evaluation of Processing and Structure.

BACKGROUND: Bone grafts are used in approximately one half of all musculoskeletal surgeries. Autograft bone is the historic gold standard but is limited in supply and its harvest imparts significant morbidity to the patient. Alternative sources of bone graft include allografts, synthetics and, less commonly, xenografts which are taken from animal species. Xenografts are available in unlimited supply from healthy animal donors with controlled biology, avoiding the risk of human disease transmission, and may satisfy current demand for bone graft products. METHODS: In the current study, cancellous bone was harvested from porcine femurs and subjected to a novel decellularization protocol to derive a bone scaffold. RESULTS: The scaffold was devoid of donor cellular material on histology and DNA sampling (p < 0.01). Microarchitectural properties important for osteoconductive potential were preserved after decellularization as shown by high resolution imaging modalities. Proteomics data demonstrated similar profiles when comparing the porcine bone scaffold against commercially available human demineralized bone matrix approved for clinical use. CONCLUSION: We are unaware of any porcine-derived bone graft products currently used in orthopaedic surgery practice. Results from the current study suggest that porcine-derived bone scaffolds warrant further consideration to serve as a potential bone graft substitute.

Microspheres containing decellularized cartilage induce chondrogenesis in vitro and remain functional after incorporation within a poly(caprolactone) filament useful for fabricating a 3D scaffold.

In this study, articular cartilage was decellularized preserving a majority of the inherent proteins, cytokines, growth factors and sGAGs. The decellularized cartilage matrix (dCM) was then encapsulated in poly(lactic acid) microspheres (MS + dCM) via double emulsion. Blank microspheres without dCM, MS(-), were also produced. The microspheres were spherical in shape and protein encapsulation efficiency within MS + dCM was 63.4%. The sustained release of proteins from MS + dCM was observed over 4 weeks in vitro. Both MS + dCM and MS(-) were cytocompatible. The sustained delivery of retained growth factors and cytokines from MS + dCM promoted cell migration in contrast to MS(-). Subsequently, chondrogenesis of human mesenchymal stem cells was upregulated in presence of MS + dCM as evidenced from immunohistochemistry, biochemical quantification and qPCR studies. Specifically, collagen II, aggrecan and SOX 9 gene expression were increased in the presence of MS + dCM by an order or more in magnitude compared to MS(-) with concomitant downregulation of hypertrophic genes (COL X) despite being cultured in the absence of chondrogenic media, (p < 0.05). Lastly, microspheres containing alkaline phosphatase (MS + ALP), a surrogate to assess the thermal stability of dCM proteins, incorporated within poly(caprolactone) filaments showed that the enzyme remained functional after filament production by melt extrusion. The establishment of a novel, thermally stable process for producing filaments containing chondroinductive microspheres provides evidence supporting subsequent development of a clinically-relevant, 3D scaffold fabricated from them for osteochondral regeneration and repair.

The Development of a Xenograft-Derived Scaffold for Tendon and Ligament Reconstruction Using a Decellularization and Oxidation Protocol.

PURPOSE: To evaluate the biological, immunological, and biomechanical properties of a scaffold derived by architectural modification of a fresh-frozen porcine patella tendon using a decellularization protocol that combines physical, chemical, and enzymatic modalities. METHODS: Porcine patellar tendons were processed using a decellularization and oxidation protocol that combines physical, chemical, and enzymatic modalities. Scaffolds (n = 88) were compared with native tendons (n = 70) using histologic, structural (scanning electron microscopy, porosimetry, and tensile testing), biochemical (mass spectrometry, peracetic acid reduction, DNA quantification, alpha-galactosidase [α-gal] content), as well as in vitro immunologic (cytocompatibility, cytokine induction) and in vivo immunologic nonhuman primate analyses. RESULTS: A decrease in cellularity based on histology and a significant decrease in DNA content were observed in the scaffolds compared with the native tendon (P < .001). Porosity and pore size were increased significantly (P < .001). Scaffolds were cytocompatible in vitro. There was no difference between native tendons and scaffolds when comparing ultimate tensile load, stiffness, and elastic modulus. The α-gal xenoantigen level was significantly lower in the decellularized scaffold group compared with fresh-frozen, nondecellularized tissue (P < .001). The in vivo immunological response to implanted scaffolds measured by tumor necrosis factor-α and interleukin-6 levels was significantly (P < .001) reduced compared with untreated controls in vitro. These results were confirmed by an attenuated response to scaffolds in vivo after implantation in a nonhuman primate model. CONCLUSIONS: Porcine tendon was processed via a method of decellularization and oxidation to produce a scaffold that possessed significantly less inflammatory potential than a native tendon, was biocompatible in vitro, of increased porosity, and with significantly reduced amounts of α-gal epitope while retaining tensile properties. CLINICAL RELEVANCE: Porcine-derived scaffolds may provide a readily available source of material for musculoskeletal reconstruction and repair while eliminating concerns regarding disease transmission and the morbidity of autologous harvest.

Intraoperative Evaluation of Acetabular Morphology in Hip Arthroscopy Comparing Standard Radiography Versus Fluoroscopy: A Cadaver Study.

PURPOSE: To compare quantitative measurements of acetabular morphology obtained using intraoperative fluoroscopy, to standardized anteroposterior (AP) pelvis radiographs. METHODS: Ten dried human pelvis specimens (20 hips) were imaged using hip-centered fluoroscopy and standardized AP pelvis radiographs. Each hip was evaluated for acetabular version and coverage, including lateral center edge (LCE) angle, acetabular index (AI), total anterior and posterior coverage, and crossover sign. RESULTS: No statistically significant differences existed between the mean LCE angle (fluoroscopy 36.5° ± 8.3° v plain films 36.1° ± 7.9°, P = .59), acetabular index (0.6° ± 8.6° v 0.2° ± 7.1°, P = .61), ACM angle (44.0° ± 2.6° v 44.1° ± 3.8°, P = .89), Sharp's angle (31.8° ± 5.7° v 32.4° ± 3.9°, P = .44), and the total femoral coverage (80.9% ± 6.4% v 80.7% ± 7.5%, P = .83). Conversely, total anterior coverage (30.7% ± 8.5% v 33.3% ± 8.2%, P < .0001) appeared significantly decreased and the total posterior coverage (54.1% ± 6.9% v 49.1% ± 7.8%, P < .0001) appeared significantly increased in fluoroscopy compared with plain film radiographs. Fluoroscopy also failed to identify the presence of a crossover sign in 30% and underestimated the retroversion index (9% ± 16%, v 13% ± 16%, P = .016). CONCLUSIONS: The values for the LCE angle and AI determined by hip-centered fluoroscopy did not differ from those obtained by standardized AP plain film radiography. However, fluoroscopy leads to a more anteverted projection of the acetabulum with significantly decreased total anterior coverage, significantly increased total posterior coverage, and underestimated signs of retroversion compared with standardized AP pelvis radiography. CLINICAL RELEVANCE: This study shows reliable LCE and AI angles but significant differences in the projected anteversion of the acetabulum between standardized AP pelvis radiography and hip-centered fluoroscopy.

Effect of cyclic strain on tensile properties of a naturally derived, decellularized tendon scaffold seeded with allogeneic tenocytes and associated messenger RNA expression.

Naturally derived tendon scaffolds have the potential to improve the treatment of flexor tendon injuries. Seeded and unseeded tendon scaffolds were maintained in the presence or absence of physiologic strain for 7 days. After 7 days, the tensile properties and associated messenger RNA expression were compared. Seeded scaffolds maintained in the absence of strain had significantly lower tensile properties than unseeded tendons and fresh-frozen tendons. The loss of tensile properties was associated with elevated matrix metalloproteinase-2 and collagen III expression. Tensile properties of seeded scaffolds maintained in the presence of strain for 7 days after seeding did not differ from those of fresh-frozen tendons. This study demonstrates that the tensile properties of seeded, naturally derived tendon scaffolds will degrade rapidly in the absence of cyclic strain. Seeded scaffolds used for tendon reconstruction should be maintained under cyclic strain to maintain essential tensile properties.

The science of rotator cuff tears: translating animal models to clinical recommendations using simulation analysis.

PURPOSE: The purpose of this article is to review basic science studies using various animal models for rotator cuff research and to describe structural, biomechanical, and functional changes to muscle following rotator cuff tears. The use of computational simulations to translate the findings from animal models to human scale is further detailed. METHODS: A comprehensive review was performed of the basic science literature describing the use of animal models and simulation analysis to examine muscle function following rotator cuff injury and repair in the ageing population. RESULTS: The findings from various studies of rotator cuff pathology emphasize the importance of preventing permanent muscular changes with detrimental results. In vivo muscle function, electromyography, and passive muscle-tendon unit properties were studied before and after supraspinatus tenotomy in a rodent rotator cuff injury model (acute vs chronic). Then, a series of simulation experiments were conducted using a validated computational human musculoskeletal shoulder model to assess both passive and active tension of rotator cuff repairs based on surgical positioning. CONCLUSION: Outcomes of rotator cuff repair may be improved by earlier surgical intervention, with lower surgical repair tensions and fewer electromyographic neuromuscular changes. An integrated approach of animal experiments, computer simulation analyses, and clinical studies may allow us to gain a fundamental understanding of the underlying pathology and interpret the results for clinical translation.

A novel process for optimizing musculoskeletal allograft tissue to improve safety, ultrastructural properties, and cell infiltration.

BACKGROUND: This study evaluated the properties of scaffold derived from freeze-dried human Achilles tendon allograft for use in anterior cruciate ligament (ACL) reconstruction. Our hypothesis was that such an allograft could be processed using a method to remove cellular and infectious material, producing a cytocompatible, architecturally modified scaffold possessing tensile properties suitable for ACL reconstruction. METHODS: Fifty-two allografts were provided by a tissue bank. Twenty-one were used as controls to assess cellularity, DNA content, microarchitecture, porosity, cytocompatibility, and tensile properties in vitro (n = 13) and in vivo (n = 8). Thirty-one were processed to produce scaffolds that were similarly assessed for these properties in vitro (n = 23) and in vivo (n = 8). The elimination of added enveloped and nonenveloped viruses was also determined in vitro after each processing step. RESULTS: A subjective decrease in cellularity and a significant decrease in DNA content were observed in the scaffolds compared with the allografts from which they had been derived. The porosity was increased significantly, and the scaffolds were cytocompatible in vitro. Processing resulted in significantly increased elongation of the scaffolds (138% of the elongation of the unprocessed allograft) during tensile testing. No other significant differences in tensile properties were observed in vitro or in vivo. The number of infiltrating host cells and the depth to which those cells infiltrated were significantly greater in the scaffolds. No enveloped viruses and only two of 10(8) nonenveloped viruses were detected in the scaffolds after processing, corresponding to a sterility assurance level of 0.2 × 10(-7). CONCLUSIONS: Allografts were processed using a method that removed cellular and infectious material to produce a decellularized, cytocompatible, architecturally modified scaffold with tensile properties that differed minimally from those of human allograft tissue both in vitro and in vivo. The scaffold production process also resulted in an increase in porosity that led to increased cell infiltration in vivo.