Identifying Anterior Cruciate Ligament Injuries Through Automated Video Analysis of In-Game Motion Patterns.

Background: Failure to diagnose anterior cruciate ligament (ACL) injury during a game can delay adequate treatment and increase the risk of further injuries. Artificial intelligence (AI) has the potential to be an accurate, cost-efficient, and readily available diagnostic tool for ACL injury in in-game situations. Purpose: To develop an automated video analysis system that uses AI to identify biomechanical patterns associated with ACL injury and to evaluate whether the system can enhance the ability of orthopaedic and sports medicine specialists to identify ACL injuries on video. Study Design: Descriptive laboratory study. Methods: A total of 91 ACL injury and 38 control movement scenes from online available match recordings were analyzed. The videos were processed to identify and track athletes and to estimate their 3-dimensional (3D) poses. Geometric features, including knee flexion, knee and hip abduction, and foot and hip rotation, were extracted from the athletes' 3D poses. A recurrent neural network algorithm was trained to classify ACL injury, using these engineered features as its input. Analysis by 2 orthopaedic surgeons examined whether providing clinical experts with the reconstructed 3D poses and their derived signals could increase their diagnostic accuracy. Results: All AI models performed significantly better than chance. The best model, which used the long short-term memory network with engineered features, demonstrated decision interpretability and good performance (F1 score = 0.63 ± 0.01, area under the receiver operating characteristic curve = 0.88 ± 0.01). The analysis by the 2 orthopaedic surgeons demonstrated improved diagnostic accuracy for ACL injury recognition when provided with system data, resulting in a 0.08 increase in combined F1 scores. Conclusion: Our approach successfully reconstructed the 3D motion of athletes from a single-camera view and derived geometry-based biomechanical features from pose sequences. Our trained AI model was able to automatically detect ACL injuries with relatively good performance and prelabel and highlight regions of interest in video footage. Clinical Relevance: This study demonstrated the feasibility of using AI to automatically evaluate in-game video footage and identify dangerous motion patterns. Further research can explore the full potential of the biomechanical markers and use of the system by nonspecialists, potentially diminishing the rate of missed diagnosis and the detrimental outcomes that follow.

Effect of Tibiofemoral Rotation Angle on Graft Failure After Anterior Cruciate Ligament Reconstruction.

BACKGROUND: Coronal and sagittal malalignment of the knee are well-recognized risk factors for failure after anterior cruciate ligament (ACL) reconstruction (ACLR). However, the effect of axial malalignment on graft survival after ACLR is yet to be determined. PURPOSE: To evaluate whether increased tibiofemoral rotational malalignment, namely, tibiofemoral rotation angle (TFA) and tibial tubercle-trochlear groove (TT-TG) distance, is associated with graft failure after ACLR. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: In this retrospective matched control study of a single center's database, 151 patients who underwent revision ACLR because of graft failure (ACLR failure group, defined as symptomatic patients with anterior knee instability and an ACL graft tear appreciated on magnetic resonance imaging [MRI] and confirmed during arthroscopic surgery) were compared with a matched control group of 151 patients who underwent primary ACLR with no evidence of failure after ≥2-year follow-up (intact ACLR group). Patients were matched by sex, age, and meniscal injury during primary ACLR. Axial malalignment was assessed on preoperative MRI through the TFA and the TT-TG distance. Sagittal alignment was measured through the posterior tibial slope on MRI. The optimal TFA cutoff associated with graft failure was identified by a receiver operating characteristic curve. The Kaplan-Meier curve with log-rank analysis was performed to evaluate the influence of the TFA on ACLR longevity. RESULTS: The mean age was 25.7 ± 10.4 years for the ACLR failure group and 25.9 ± 10.0 years for the intact ACLR group. Among all the included patients, 174 (57.6%) were male. In the ACLR failure group, the mean TFA was 5.8°± 4.5° (range, -5° to 16°), while it was 3.0°± 3.3° (range, -3° to 15°) in the intact ACLR group (P < .001). Neither the TT-TG distance nor the posterior tibial slope presented statistical differences between the groups. The receiver operating characteristic curve suggested an optimal TFA cutoff of 4.5° for graft failure (area under the curve = 0.71; P < .001; sensitivity, 68.2%; specificity, 75.5%). Considering this a threshold, patients who had a TFA ≥4.5° had 6.6 times higher odds of graft failure compared with patients with a TFA <4.5° (P < .001). Survival analysis demonstrated a 5-year survival rate of 81% in patients with a TFA <4.5°, while it was 44% in those with a TFA ≥4.5° (P < .001). CONCLUSION: An increased TFA was associated with increased odds of ACLR failure when the TFA was ≥4.5°. Measuring the TFA in patients with ACL tears undergoing reconstruction may inform the surgeon about additional factors that may require consideration before ACLR for a successful outcome.

Return to Play After Shoulder Surgery in Professional Baseball Players: A Systematic Review and Meta-analysis.

Background: The current literature lacks an updated review examining return to play (RTP) and return to prior performance (RTPP) after shoulder surgery in professional baseball players. Purpose: To summarize the RTP rate, RTPP rate, and baseball-specific performance metrics among professional baseball players who underwent shoulder surgery. Study Design: Systematic review; Level of evidence, 4. Methods: A literature search was performed utilizing the PubMed, MEDLINE, and CINAHL databases and according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Inclusion criteria were English-language studies reporting on postoperative RTP and/or RTPP in professional baseball players who underwent shoulder surgery between 1976 and 2016. RTP rates, RTPP rates, and baseball-specific performance metrics were extracted from qualifying studies. A total of 2034 articles were identified after the initial search. Meta-analysis was performed where applicable, yielding weighted averages of RTP and RTPP rates and comparisons between pitchers and nonpitchers for each type of surgery. Baseball-specific performance metrics were reported as a narrative summary. Results: Overall, 26 studies featuring 1228 professional baseball players were included. Patient-level outcome data were available for 529 players. Surgical interventions included rotator cuff debridement (n = 197), rotator cuff repair (RCR; n = 43), superior labrum from anterior to posterior repair (n = 124), labral repair (n = 103), latissimus dorsi/teres major (LD/TM) repair (n = 21), biceps tenodesis (n = 17), coracoclavicular ligament reconstruction (n = 15), anterior capsular repair (n = 5), and scapulothoracic bursectomy (n = 4). Rotator cuff debridement was the most common surgical procedure, while scapulothoracic bursectomy was the least common (37.2% and 0.8% of interventions, respectively). Meta-analysis revealed that the RTP rate was highest for LD/TM repair (84.5%) and lowest for RCR (53.5%), while the RTPP rate was highest for LD/TM repair (100.0%) and lowest for RCR (27.9%). RTP and RTPP rates were generally higher for position players than for pitchers. Nonvolume performance metrics were unaffected by shoulder surgery, while volume statistics decreased or remained similar. Conclusion: RTP and RTPP rates among professional baseball players were modest after most types of shoulder surgery. Among surgical procedures commonly performed on professional baseball players, RTP and RTPP rates were highest for LD/TM repair and lowest for RCR.

Grinding, Clicking, and Pivot Pain Resolve in Most Patients After Knee Arthroscopy.

PURPOSE: To determine whether knee arthroscopy alleviates the symptom constellation of knee grinding/clicking, catching/locking, and pivot pain. METHODS: One-year follow-up data from 584 consecutive subjects who underwent knee arthroscopy from August 2012 to December 2019 were collected prospectively. Subjects reported frequency of knee grinding/clicking, catching/locking, and/or pivot pain preoperatively and 1 and 2 years postoperatively. A single surgeon performed each procedure and documented all intraoperative pathology. We measured the postoperative resolution or persistence of these symptoms and used multivariable regression models to identify preoperative demographic and clinical variables that predicted symptom persistence. We also assessed changes in the Pain, Activities of Daily Living, and Quality of Life subscales of the Knee Injury and Osteoarthritis Outcome Score (KOOS). RESULTS: Postoperative symptom resolution was more likely for grinding/clicking (65.6%) and pivot pain (67.8%) than for catching/locking (44.1%). Smoking status, overweight/obesity, absence of meniscal tear, and number of compartments with focal cartilage lesions predicted persistence of 1 or more patient-reported knee symptoms. KOOS subscale scores consistently improved by at least one standard deviation. Individuals who had resolution of patient-reported knee symptoms exhibited roughly 2-fold improvements in KOOS Pain, ADL and Quality of Life scores compared with those whose symptoms persisted. Persistence of pivot pain was associated with the least improvement of the 3 KOOS subscales. CONCLUSIONS: Two in three patients with grinding/clicking or pivot pain experience symptom resolution after knee arthroscopy, although catching/locking is more likely to persist. Smoking status, overweight/obesity, absence of meniscal tear, and number of compartments with focal cartilage lesions predict symptom persistence after knee arthroscopy. LEVEL OF EVIDENCE: Therapeutic Level IV, retrospective cohort analysis of prospective data.

Editorial Commentary: Fascia Lata Allograft for Shoulder Superior Capsular Reconstruction: In the Fight Over Optimal Graft Choice for Irreparable Rotator Cuff Tears, Superior Capsular Reconstruction Proponents May Be Changing Their Gloves.

Optimal treatment of irreparable rotator cuff tears is still debated. Proponents of the superior capsule reconstruction (SCR) have previously used fascia lata autograft and acellular dermal allograft. Interest is growing in using fascia lata allograft as a new graft material. Well-designed biomechanical studies are important to understand the mechanical properties of the superior capsular tissue and fascia lata allograft. Recent biomechanical research shows that fascia lata allograft has similar initial stiffness (over the first 2 mm) and ultimate load compared to the native superior capsule. That said, ultimate load is the load at which a construct fails, whereas the yield point is the load on the stress-strain curve at which a material transitions from elastic to plastic deformation. In the shoulder where the SCR, for example, is going to be repetitively loaded, it is potentially more meaningful to talk about the yield point in order to stay within the elastic range. Using this framework, the yield point for fascia lata allograft is approximately one third the yield point of native capsular tissue. Additionally, "initial" stiffness is not the entire story. At greater loads, fascia lata allograft has higher displacement compared to native tissue. Of importance, fascia lata allograft failed by sutures slowly cutting through the allograft tissue; this may represent a limitation of the construct that could be addressed using stitch configurations resistant to cut through. Fascia lata allograft is a promising solution for SCR. Biomechanical studies require nuanced interpretation, and most of all, do not evaluate clinical healing.

Systematic Review of Clinical Results After Medial Meniscus Allograft Transplantation Reveals Improved Patient Reported Outcomes at Greater Than 5 Years Follow-Up.

PURPOSE: To systematically summarize the medial meniscus allograft transplantation (MAT) reported outcomes and evaluate whether the surgical technique is associated with allograft extrusion and knee function. METHODS: Systematic review was conducted according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Inclusion criteria were English-language clinical studies involving arthroscopically assisted medial MAT that reported the surgical technique and the presence of graft extrusion or functional outcomes after surgery. Studies in which outcomes for medial MAT could not be separated from lateral MAT were excluded. Surgical technique, allograft-related characteristics, and clinical outcomes were extracted. RESULTS: Twenty-four studies with 328 medial MAT were included, 58.3% studies qualified as level 4 of evidence, 29.2% as level 3, and 12.5% as level 2. Allograft fixation techniques were bone plug (235/328 [71.6%]), bone bridge/trough (55/328 [16.8%]), and soft-tissue suture fixation only (38/328 [11.6%]). Relative percentage of extrusion after surgery ranged from 24.8% to 53.7%. Major extrusion (>3 mm) ranged from zero to 78%. Overall, functional scores improved after medial MAT. None of surgical techniques were associated with poor functional outcomes or extruded meniscus; however, nonanatomical placement of the anterior and posterior horns appeared to increase meniscus extrusion. CONCLUSION: Medial MAT provides favorable outcomes, with acceptable rates of complication and failure regardless of surgical technique. Although allograft extrusion appears equivalent for both bone plug and soft-tissue fixation techniques, positioning allograft horns at the native meniscal footprint may be critical for preventing extrusion. However, the heterogeneity and low level of evidence of the studies included in this review prevent decisive conclusions regarding optimal MAT fixation techniques, clinical significance of allograft extrusion, or comparative clinical outcomes after medial MAT. LEVEL OF EVIDENCE: Level IV - systematic review of Level II to IV studies.

Harvest Technique Does Affect the Quality of Osteochondral Grafts: Histologic Evaluation Comparing Commercial Standards versus Scalpel Blade Technique.

OBJECTIVE: While the percentage of viable cells is a major determinant of graft performance during osteochondral allograft (OCA) transplantation, the baseline chondrocyte viability at the periphery of osteochondral plugs is defined at the time of harvest. In this laboratory study, we aimed to determine the optimal technique for OCA plug harvest by evaluating commercial standard techniques compared to sharp blade harvest technique. DESIGN: Osteochondral explants were harvested from bovine and human samples using 3 different techniques: (1) standard OATS manual punch device (Osteochondral Autograft Transplant System OATS; Arthrex, Naples, FL), (2) powered trephine device, and (3) fresh scalpel blade. Chondrocyte viability and the dead area at the periphery of the tissue were evaluated by LIVE/DEAD staining. Safranin-O and fast-green were performed for structural evaluation. RESULTS: For both bovine and human samples, the dead area at the periphery of the explant was significantly smaller after scalpel blade preparation compared to harvest with OATS (P < 0.001) and powered trephine devices (P < 0.001). In addition, while powered device had a smaller remaining dead area compared to the OATS device (P < 0.001), there was significantly greater tissue loss and peripheral contour change for plugs harvested with the powered trephine device. CONCLUSION: Our study demonstrated that OCA plugs harvested with OATS and powered device lead to a significant mechanical injury at the periphery of the explants compared to a scalpel. We propose that the optimal technique for OCA harvest utilizes a combined approach incorporating a scalpel blade/circular scalpel to prepare the chondral surface and a powered trephine to prepare the osseous surface.

Quality of MIS vs Open Joint Preparations of the Foot and Ankle.

BACKGROUND: Minimally invasive surgery (MIS) is growing in the field of foot and ankle, and the MIS burr is an emerging tool. Although commonly used to perform osteotomies, the burr can also be used for arthrodesis joint preparation that traditionally would be performed through open incisions. To date, there is no study comparing the quality of joint preparation between using a fluoroscopy-guided MIS technique compared to traditional open techniques. The goal of this cadaveric study is to compare the percentage of joint surfaces prepared between MIS and open techniques for the most common joints that are fused in foot and ankle surgery. METHODS: Open joint preparation was performed under direct visualization with open incisions. MIS joint preparation was performed percutaneously using fluoroscopic guidance alone, without arthroscopy. After joint preparation, cadaveric samples were disarticulated, and joint surfaces were analyzed for percentage of cartilaginous surface removed. The percentage of joint surface prepared was compared between the open and MIS techniques. RESULTS: Ten cadaveric samples were used for the MIS technique and 5 samples for the open technique. Percentage of joint surface prepared was similar for all joint surfaces. CONCLUSION: The MIS technique in the hands of experienced surgeons was found to provide overall similar percentages of surface area prepared compared to traditional open techniques. CLINICAL RELEVANCE: MIS joint preparation may be useful for specific patient populations. This study suggests that MIS joint preparation is a reasonable, and possibly advantageous, alternative to open preparation in arthrodesis surgery when performed by experienced MIS surgeons.

Association of Sex Mismatch Between Donor and Recipient With Graft Survivorship at 5 Years After Osteochondral Allograft Transplantation.

BACKGROUND: Sex mismatch between donor and recipient has been considered a potential contributor to adverse outcomes after solid organ transplantation. However, the influence of sex mismatching in osteochondral allograft (OCA) transplantation has yet to be determined. PURPOSE: To evaluate whether donor-recipient sex mismatching affects graft survival after OCA transplantation. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: In this review of prospectively collected data, patients who underwent OCA transplantation between November 2013 and November 2017 by a single surgeon were analyzed. Cumulative survival was assessed via the Kaplan-Meier method using log-rank tests to compare patients with similar donor groups. Multivariable Cox regression analysis adjusted for patient age, graft size, and body mass index was used to evaluate the influence of donor-recipient sex on graft survival. RESULTS: A total of 154 patients were included: 102 (66.2%) who received OCAs from a same-sex donor and 52 (33.8%) who received OCAs from a different-sex donor. At 5-year follow-up, a significantly lower graft survival rate was observed for different-sex donor transplantation in comparison with same-sex donorship (63% vs 92%; P = .01). When correcting for age, graft size, and body mass index, donor-recipient sex-mismatch transplantation demonstrated a 2.9-times greater likelihood to fail at 5 years compared with donor-recipient same-sex transplantation (95% CI, 1.11-7.44; P = .03). A subgroup analysis showed no significant difference in graft survival between the female-to-female and female-to-male groups (91% and 84%, respectively). Conversely, male-to-male transplantation demonstrated a significantly higher cumulative 5-year survival (94%; P = .04), whereas lower survival was found with male-to-female donorship (64%; P = .04). Multivariable Cox regression indicated a 2.6-times higher likelihood of failure for the male-to-female group in comparison with the other groups (95% CI, 1.03-6.69; P = .04). Male-to-male transplantation had a tendency toward decreased likelihood of OCA failure (hazard ratio, 0.33), although without statistical significance (95% CI, 0.11-1.01; P = .052). CONCLUSION: Mismatch between donor and recipient sex had a negative effect on OCA survival after transplantation, particularly in those cases when male donor tissue was transplanted into a female recipient.

Meniscal and Mechanical Symptoms Are Associated with Cartilage Damage, Not Meniscal Pathology.

BACKGROUND: Traditionally defined "meniscal" and "mechanical" symptoms are thought to arise from meniscal tears. Yet meniscal tears and cartilage damage commonly coexist in symptomatic knees. To better characterize the primary driver of these symptoms, we investigated whether the presence of preoperative patient-reported knee symptoms (PRKS), including knee catching/locking, grinding/clicking/popping, and pain with pivoting, are associated with various intra-articular pathological conditions diagnosed at knee arthroscopy. METHODS: We collected prospective data from 565 consecutive patients who underwent knee arthroscopy from 2012 to 2019 and had PRKS collected via the Knee injury and Osteoarthritis Outcome Score (KOOS) questionnaire. The diagnosis of meniscal pathology and concomitant cartilage damage was confirmed and classified intraoperatively. We used multivariable regression models, adjusting for possible confounders, to examine the association of specific pathological conditions of the knee with the presence of preoperative PRKS. RESULTS: Tricompartmental cartilage damage was strongly associated with significantly worse PRKS, with an increase of 0.33 point (95% confidence interval [CI] = 0.08 to 0.58; p = 0.01) on a 0 to 4-point scale. We did not observe an association between meniscal pathology and preoperative PRKS. CONCLUSIONS: Contrary to current dogma, this study demonstrates that traditionally defined "meniscal" and "mechanical" knee symptoms are strongly associated with the burden and severity of underlying cartilage damage rather than with specific meniscal pathology. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Shorter Storage Time Is Strongly Associated With Improved Graft Survivorship at 5 Years After Osteochondral Allograft Transplantation.

BACKGROUND: Current regulations surrounding the use of osteochondral allografts (OCAs) in the United States require delayed graft release after 14 days to complete infectious disease screening. With a generally accepted expiration time of 28 days in storage, a limited window from 14 to 28 days remains for implantation. Yet, the rates of graft survival and thus optimal time for transplantation within this window remain largely unknown. HYPOTHESIS: OCAs transplanted within 19 to 24 days would have lower failure rates at 5 years than those transplanted at 25 to 27 days. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: In this retrospective case series, we analyzed data from patients who underwent OCA transplantation (N = 111) by a single surgeon between February 2014 and December 2016 with at least 2-year follow-up. In total, 56 patients received early transplant grafts (storage time, 19-24 days), and 55 received late transplant grafts (storage time, 25-27 days). Survival analysis with Kaplan-Meier curves was performed using log-rank analysis to compare the groups. Multivariable Cox regression analysis was used to assess the influence of OCA storage duration on graft survival while adjusting for age and defect size. Optimal storage time cutoff associated with graft failure was identified by performing receiver operating characteristic curve analysis and calculating the area under the curve. RESULTS: Patients in the late transplant group had a significantly lower rate of graft survival at 5 years postoperatively (70.4%) as compared with patients in the early transplant group (93.1%; P = .027). When correcting for patient age and defect size, late transplant OCAs demonstrated a 3.4-times greater likelihood of failure versus early transplant OCAs. Receiver operating characteristic analysis suggested that OCA transplantation should ideally occur before 25 days of graft storage. CONCLUSION: OCA transplantation is a safe and successful treatment option for large osteochondral defects of the knee, with excellent rates of in situ graft survival at 5 years. Prioritizing early transplantation of OCAs to <25 days in storage improves rates of graft survival.

Adenovirus-Mediated Gene Delivery: Potential Applications for Gene and Cell-Based Therapies in the New Era of Personalized Medicine.

With rapid advances in understanding molecular pathogenesis of human diseases in the era of genome sciences and systems biology, it is anticipated that increasing numbers of therapeutic genes or targets will become available for targeted therapies. Despite numerous setbacks, efficacious gene and/or cell-based therapies still hold the great promise to revolutionize the clinical management of human diseases. It is wildly recognized that poor gene delivery is the limiting factor for most in vivo gene therapies. There has been a long-lasting interest in using viral vectors, especially adenoviral vectors, to deliver therapeutic genes for the past two decades. Among all currently available viral vectors, adenovirus is the most efficient gene delivery system in a broad range of cell and tissue types. The applications of adenoviral vectors in gene delivery have greatly increased in number and efficiency since their initial development. In fact, among over 2,000 gene therapy clinical trials approved worldwide since 1989, a significant portion of the trials have utilized adenoviral vectors. This review aims to provide a comprehensive overview on the characteristics of adenoviral vectors, including adenoviral biology, approaches to engineering adenoviral vectors, and their applications in clinical and pre-clinical studies with an emphasis in the areas of cancer treatment, vaccination and regenerative medicine. Current challenges and future directions regarding the use of adenoviral vectors are also discussed. It is expected that the continued improvements in adenoviral vectors should provide great opportunities for cell and gene therapies to live up to its enormous potential in personalized medicine.

Bone morphogenetic protein 9 (BMP9) induces effective bone formation from reversibly immortalized multipotent adipose-derived (iMAD) mesenchymal stem cells.

Regenerative medicine and bone tissue engineering using mesenchymal stem cells (MSCs) hold great promise as an effective approach to bone and skeletal reconstruction. While adipose tissue harbors MSC-like progenitors, or multipotent adipose-derived cells (MADs), it is important to identify and characterize potential biological factors that can effectively induce osteogenic differentiation of MADs. To overcome the time-consuming and technically challenging process of isolating and culturing primary MADs, here we establish and characterize the reversibly immortalized mouse multipotent adipose-derived cells (iMADs). The isolated mouse primary inguinal MAD cells are reversibly immortalized via the retrovirus-mediated expression of SV40 T antigen flanked with FRT sites. The iMADs are shown to express most common MSC markers. FLP-mediated removal of SV40 T antigen effectively reduces the proliferative activity and cell survival of iMADs, indicating the immortalization is reversible. Using the highly osteogenic BMP9, we find that the iMADs are highly responsive to BMP9 stimulation, express multiple lineage regulators, and undergo osteogenic differentiation in vitro upon BMP9 stimulation. Furthermore, we demonstrate that BMP9-stimulated iMADs form robust ectopic bone with a thermoresponsive biodegradable scaffold material. Collectively, our results demonstrate that the reversibly immortalized iMADs exhibit the characteristics of multipotent MSCs and are highly responsive to BMP9-induced osteogenic differentiation. Thus, the iMADs should provide a valuable resource for the study of MAD biology, which would ultimately enable us to develop novel and efficacious strategies for MAD-based bone tissue engineering.

A thermoresponsive polydiolcitrate-gelatin scaffold and delivery system mediates effective bone formation from BMP9-transduced mesenchymal stem cells.

Successful bone tissue engineering requires at the minimum sufficient osteoblast progenitors, efficient osteoinductive factors, and biocompatible scaffolding materials. We previously demonstrated that bone morphogenetic protein 9 (BMP9) is one of the most potent factors in inducing osteogenic differentiation of mesenchymal stem cells (MSCs). Here, we investigated the potential use of a biodegradable citrate-based thermosensitive macromolecule, poly(polyethyleneglycol citrate-co-N-isopropylacrylamide) (PPCN) mixed with gelatin (PPCNG) as a scaffold for the delivery of BMP9-stimulated MSCs to promote localized bone formation. The addition of gelatin to PPCN effectively enhanced the cell adhesion and survival properties of MSCs entrapped within the gel in 3D culture. Using the BMP9-transduced MSC line immortalized mouse embryonic fibroblasts (iMEFs), we found that PPCNG facilitated BMP9-induced osteogenic differentiation of iMEFs in vivo and promoted the formation of well-ossified and vascularized trabecular bone-like structures in a mouse model of ectopic bone formation. Histologic evaluation revealed that vascularization of the bony masses retrieved from the iMEFs + PPCNG group was significantly more pronounced than that of the direct cell injection group. Accordingly, vascular endothelial growth factor (VEGF) expression was shown to be significantly higher in the bony masses recovered from the iMEFs + PPCNG group. Taken together, our results suggest that PPCNG may serve as a novel biodegradable and injectable scaffold and carrier for gene and cell-based bone tissue engineering.

Molecular basis of cranial suture biology and disease: Osteoblastic and osteoclastic perspectives.

The normal growth and development of the skull is a tightly regulated process that occurs along the osteogenic interfaces of the cranial sutures. Here, the borders of the calvarial bones and neighboring tissues above and below, function as a complex. Through coordinated remodeling efforts of bone deposition and resorption, the cranial sutures maintain a state of patency from infancy through early adulthood as the skull continues to grow and accommodate the developing brain's demands for expansion. However, when this delicate balance is disturbed, a number of pathologic conditions ensue; and if left uncorrected, may result in visual and neurocognitive impairments. A prime example includes craniosynostosis, or premature fusion of one or more cranial and/or facial suture(s). At the present time, the only therapeutic measure for craniosynostosis is surgical correction by cranial vault reconstruction. However, elegant studies performed over the past decade have identified several genes critical for the maintenance of suture patency and induction of suture fusion. Such deeper understandings of the pathogenesis and molecular mechanisms that regulate suture biology may provide necessary insights toward the development of non-surgical therapeutic alternatives for patients with cranial suture defects. In this review, we discuss the intricate cellular and molecular interplay that exists within the suture among its three major components: dura mater, osteoblastic related molecular pathways and osteoclastic related molecular pathways.

Fibroblast growth factor (FGF) signaling in development and skeletal diseases.

Fibroblast growth factors (FGF) and their receptors serve many functions in both the developing and adult organism. Humans contain 18 FGF ligands and four FGF receptors (FGFR). FGF ligands are polypeptide growth factors that regulate several developmental processes including cellular proliferation, differentiation, and migration, morphogenesis, and patterning. FGF-FGFR signaling is also critical to the developing axial and craniofacial skeleton. In particular, the signaling cascade has been implicated in intramembranous ossification of cranial bones as well as cranial suture homeostasis. In the adult, FGFs and FGFRs are crucial for tissue repair. FGF signaling generally follows one of three transduction pathways: RAS/MAP kinase, PI3/AKT, or PLCγ. Each pathway likely regulates specific cellular behaviors. Inappropriate expression of FGF and improper activation of FGFRs are associated with various pathologic conditions, unregulated cell growth, and tumorigenesis. Additionally, aberrant signaling has been implicated in many skeletal abnormalities including achondroplasia and craniosynostosis. The biology and mechanisms of the FGF family have been the subject of significant research over the past 30 years. Recently, work has focused on the therapeutic targeting and potential of FGF ligands and their associated receptors. The majority of FGF-related therapy is aimed at age-related disorders. Increased understanding of FGF signaling and biology may reveal additional therapeutic roles, both in utero and postnatally. This review discusses the role of FGF signaling in general physiologic and pathologic embryogenesis and further explores it within the context of skeletal development.