Is SSRI use a risk factor for intracranial hemorrhage after craniotomy for tumor resection?

Introduction: Prior studies have identified SSRI use as a risk factor for certain adverse bleeding outcomes. However, the risk of significant bleeding from perioperative SSRI use after brain tumor resection remains largely undetermined. This study evaluates if patients taking SSRIs perioperatively have a higher risk of intracranial hemorrhage (ICH) following elective craniotomy for tumor resection. Methods: Researchers reviewed electronic medical records of patients age 18 and older, who received elective craniotomy for tumor resection between 2010 and 2019. Data collection included subject demographics and relevant medical history. We compared intracranial hemorrhage rates and risks between perioperative SSRI-use cohorts. Results: Of 1,061 patients, 796 (75%) did not use SSRIs perioperatively while 265 (25%) used SSRIs perioperatively. Among those using perioperative SSRIs, 8 patients (3.0%) experienced an ICH within 1 week and 11 patients (4.2%) had an ICH within 1 month. Similarly, for those who stopped SSRI use perioperatively, we found 31 patients (3.9%) experienced an ICH within 1 week and 40 patients (5.0%) had an ICH within 1 month. Using logistic regression analysis, the relative risk for perioperative SSRI-use and ICH was statistically non-significant at 0.692 (95% CI: 0.260 - 1.839, p = 0.460). Conclusions: Based on our results, perioperative SSRI use does not appear to result in an increased risk of bleeding within 1 week or month of craniotomy for tumor resection. These results remained consistent when controlled for several additional bleeding comorbidities and demographics between cohorts.

Diffuse Midline H3K27-Altered Gliomas in the Spinal Cord: A Systematic Review.

PURPOSE: To systematically review the clinical features, management, and outcomes of diffuse midline H3K27-altered gliomas of the spinal cord (DMG-SCs). METHODS: PubMed, Ovid EMBASE, Scopus, and Web of Science were searched from database inception to 23 September 2023 for histologically confirmed cases of DMG-SC. Patient demographics, tumor characteristics, management information, and survival outcomes were extracted and analyzed. RESULTS: A total of 279 patients from 39 studies were collected. Patients were mostly male (61%), with an average age of 32 years. Patients were treated with surgery, radiotherapy, and chemotherapy combined (31%) or surgery only (24%), and extent of resection was most often subtotal (38%). Temozolomide was the most common chemotherapeutic agent (81%). Radiation therapy was delivered with mean dose of 47 Gy in 23 fractions. At mean follow-up time of 21 months, 13% of patients were alive. Average median overall survival was 24 months (range of 13 to 40 months) with a median progression-free survival of 14 months. Historical WHO grades of 2 or 3 appeared to exhibit a longer average median overall survival time than that of grade 4 DMG-SCs (32 vs. 23 months, p = 0.009). CONCLUSIONS: Outcomes for DMG-SCs are poor overall but appear to be favorable compared to intracranial DMGs. Despite the recent WHO 2021 grade 4 classification for all DMGs, given the differences in overall survival reported based on historical grading systems, future studies on DMG-SCs are needed to further define if DMG-SCs may represent a heterogeneous group of tumors with different prognoses.

Infraclavicular de novo placement of a responsive neurostimulator for a patient with eloquent glioma-associated epilepsy: illustrative case.

BACKGROUND: The authors present a 50-year-old female with high-grade glioma involving the motor cortex as the cause of her drug-resistant epilepsy (DRE). Responsive neurostimulation (RNS) was chosen for epilepsy treatment. Due to concerns regarding the generator impeding the regular imaging surveillance required for treatment and monitoring of her glioma, surgeons placed the internal pulse generator (IPG) within an infraclavicular chest pocket. OBSERVATIONS: Implantation of the RNS device and IPG within the infraclavicular pocket was uneventful. However, both subdural and depth electrodes were used and connected to the IPG, and subdural electrodes are considerably shorter than depth electrodes (37 vs 44 cm). The shorter strip leads presumably generated significant tension, leading to fracture of the leads. Therefore, surgery was repeated using only depth electrodes for more length and less tension. The device has good-quality electrocorticography signals that continue to be used for device programming. The seizure burden was reduced, and quality of life improved for the patient. LESSONS: The RNS system with infraclavicular IPG placement reduced the seizure burden and improved the quality of life of a patient with glioma-associated epilepsy. Surgeons may consider the infraclavicular location as an alternative site for implantation for RNS candidates who require recurrent intracranial magnetic resonance imaging.

Effect of Cognitive Reserve on Physiological Measures of Cognitive Workload in Older Adults with Cognitive Impairments.

BACKGROUND: Cognitive reserve may protect against cognitive decline. OBJECTIVE: This cross-sectional study investigated the association between cognitive reserve and physiological measures of cognitive workload in older adults with cognitive impairment. METHODS: 29 older adults with cognitive impairment (age: 75±6, 11 (38%) women, MoCA: 20±7) and 19 with normal cognition (age: 74±6; 11 (58%) women; MoCA: 28±2) completed a working memory test of increasing task demand (0-, 1-, 2-back). Cognitive workload was indexed using amplitude and latency of the P3 event-related potential (ERP) at electrode sites Fz, Cz, and Pz, and changes in pupillary size, converted to an index of cognitive activity (ICA). The Cognitive Reserve Index questionnaire (CRIq) evaluated Education, Work Activity, and Leisure Time as a proxy of cognitive reserve. Linear mixed models evaluated the main effects of cognitive status, CRIq, and the interaction effect of CRIq by cognitive status on ERP and ICA. RESULTS: The interaction effect of CRIq total score by cognitive status on P3 ERP and ICA was not significant. However, higher CRIq total scores were associated with lower ICA (p = 0.03). The interaction effects of CRIq subscores showed that Work Activity affected P3 amplitude (p = 0.03) and ICA (p = 0.03) differently between older adults with and without cognitive impairments. Similarly, Education affected ICA (p = 0.02) differently between the two groups. No associations were observed between CRIq and P3 latency. CONCLUSION: Specific components of cognitive reserve affect cognitive workload and neural efficiency differently in older adults with and without cognitive impairments.

EEG/ERP evidence of possible hyperexcitability in older adults with elevated beta-amyloid.

BACKGROUND: Although growing evidence links beta-amyloid (Aß) and neuronal hyperexcitability in preclinical mouse models of Alzheimer's disease (AD), a similar association in humans is yet to be established. The first aim of the study was to determine the association between elevated Aß (Aß+) and cognitive processes measured by the P3 event-related potential (ERP) in cognitively normal (CN) older adults. The second aim was to compare the event-related power between CNAß+ and CNAß-. METHODS: Seventeen CNAß+ participants (age: 73 ± 5, 11 females, Montreal Cognitive Assessment [MoCA] score 26 ± 2) and 17 CNAß- participants group-matched for age, sex, and MOCA completed a working memory task (n-back with n = 0, 1, 2) test while wearing a 256-channel electro-encephalography net. P3 peak amplitude and latency of the target, nontarget and task difference effect (nontarget-target), and event-related power in the delta, theta, alpha, and beta bands, extracted from Fz, Cz, and Pz, were compared between groups using linear mixed models. P3 amplitude of the task difference effect at Fz and event-related power in the delta band were considered main outcomes. Correlations of mean Aß standard uptake value ratios (SUVR) using positron emission tomography with P3 amplitude and latency of the task difference effect were analyzed using Pearson Correlation Coefficient r. RESULTS: The P3 peak amplitude of the task difference effect at Fz was lower in the CNAß+ group (P = 0.048). Similarly, power was lower in the delta band for nontargets at Fz in the CNAß+ participants (P = 0.04). The CNAß+ participants also demonstrated higher theta and alpha power in channels at Cz and Pz, but no changes in P3 ERP. Strong correlations were found between the mean Aß SUVR and the latency of the 1-back (r = - 0.69; P = 0.003) and 2-back (r = - 0.69; P = 0.004) of the task difference effect at channel Fz in the CNAß+ group. CONCLUSIONS: Our data suggest that the elevated amyloid in cognitively normal older adults is associated with neuronal hyperexcitability. The decreased P3 task difference likely reflects early impairments in working memory processes. Further research is warranted to determine the validity of ERP in predicting clinical, neurobiological, and functional manifestations of AD.

Functional tissue engineering of articular cartilage for biological joint resurfacing-The 2021 Elizabeth Winston Lanier Kappa Delta Award.

Biological resurfacing of entire articular surfaces represents a challenging strategy for the treatment of cartilage degeneration that occurs in osteoarthritis. Not only does this approach require anatomically sized and functional engineered cartilage, but the inflammatory environment within an arthritic joint may also inhibit chondrogenesis and induce degradation of native and engineered cartilage. Here, we present the culmination of multiple avenues of interdisciplinary research leading to the development and testing of bioartificial cartilage for tissue-engineered resurfacing of the hip joint. The work is based on a novel three-dimensional weaving technology that is infiltrated with specific bioinductive materials and/or genetically-engineered stem cells. A variety of design approaches have been tested in vitro, showing biomimetic cartilage-like properties as well as the capability for long-term tunable and inducible drug delivery. Importantly, these cartilage constructs have the potential to provide mechanical functionality immediately upon implantation, as they will need to replace a majority, if not the entire joint surface to restore function. To date, these approaches have shown excellent preclinical success in a variety of animal studies, including the resurfacing of a large osteochondral defect in the canine hip, and are now well-poised for clinical translation.

Biological resurfacing in a canine model of hip osteoarthritis.

Articular cartilage has unique load-bearing properties but has minimal capacity for intrinsic repair. Here, we used three-dimensional weaving, additive manufacturing, and autologous mesenchymal stem cells to create a tissue-engineered, bicomponent implant to restore hip function in a canine hip osteoarthritis model. This resorbable implant was specifically designed to function mechanically from the time of repair and to biologically integrate with native tissues for long-term restoration. A massive osteochondral lesion was created in the hip of skeletally mature hounds and repaired with the implant or left empty (control). Longitudinal outcome measures over 6 months demonstrated that the implant dogs returned to normal preoperative values of pain and function. Anatomical structure and functional biomechanical properties were also restored in the implanted dogs. Control animals never returned to normal and exhibited structurally deficient repair. This study provides clinically relevant evidence that the bicomponent implant may be a potential therapy for moderate hip osteoarthritis.

Chondrogenic, hypertrophic, and osteochondral differentiation of human mesenchymal stem cells on three-dimensionally woven scaffolds.

The development of mechanically functional cartilage and bone tissue constructs of clinically relevant size, as well as their integration with native tissues, remains an important challenge for regenerative medicine. The objective of this study was to assess adult human mesenchymal stem cells (MSCs) in large, three-dimensionally woven poly(ε-caprolactone; PCL) scaffolds in proximity to viable bone, both in a nude rat subcutaneous pouch model and under simulated conditions in vitro. In Study I, various scaffold permutations-PCL alone, PCL-bone, "point-of-care" seeded MSC-PCL-bone, and chondrogenically precultured Ch-MSC-PCL-bone constructs-were implanted in a dorsal, ectopic pouch in a nude rat. After 8 weeks, only cells in the Ch-MSC-PCL constructs exhibited both chondrogenic and osteogenic gene expression profiles. Notably, although both tissue profiles were present, constructs that had been chondrogenically precultured prior to implantation showed a loss of glycosaminoglycan (GAG) as well as the presence of mineralization along with the formation of trabecula-like structures. In Study II of the study, the GAG loss and mineralization observed in Study I in vivo were recapitulated in vitro by the presence of either nearby bone or osteogenic culture medium additives but were prevented by a continued presence of chondrogenic medium additives. These data suggest conditions under which adult human stem cells in combination with polymer scaffolds synthesize functional and phenotypically distinct tissues based on the environmental conditions and highlight the potential influence that paracrine factors from adjacent bone may have on MSC fate, once implanted in vivo for chondral or osteochondral repair.

Composite Cellularized Structures Created from an Interpenetrating Polymer Network Hydrogel Reinforced by a 3D Woven Scaffold.

Biomaterial scaffolds play multiple roles in cartilage tissue engineering, including controlling architecture of newly formed tissue while facilitating growth of embedded cells and simultaneously providing functional properties to withstand the mechanical environment within the native joint. In particular, hydrogels-with high water content and desirable transport properties-while highly conducive to chondrogenesis, often lack functional mechanical properties. In this regard, interpenetrating polymer network (IPN) hydrogels can provide mechanical toughness greatly exceeding that of individual components; however, many IPN materials are not biocompatible for cell encapsulation. In this study, an agarose and poly(ethylene) glycol IPN hydrogel is seeded with human mesenchymal stem cells (MSCs). Results show high viability of MSCs within the IPN hydrogel, with improved mechanical properties compared to constructs comprised of individual components. These properties are further strengthened by integrating the hydrogel with a 3D woven structure. The resulting fiber-reinforced hydrogels display functional macroscopic mechanical properties mimicking those of native articular cartilage, while providing a local microenvironment that supports cellular viability and function. These findings suggest that a fiber-reinforced IPN hydrogel can support stem cell chondrogenesis while allowing for significantly enhanced, complex mechanical properties at multiple scales as compared to individual hydrogel or fiber components.

Chondrogenic Differentiation Processes in Human Bone-Marrow Aspirates Seeded in Three-Dimensional-Woven Poly(ɛ-Caprolactone) Scaffolds Enhanced by Recombinant Adeno-Associated Virus-Mediated SOX9 Gene Transfer.

Combining gene therapy approaches with tissue engineering procedures is an active area of translational research for the effective treatment of articular cartilage lesions, especially to target chondrogenic progenitor cells such as those derived from the bone marrow. This study evaluated the effect of genetically modifying concentrated human mesenchymal stem cells from bone marrow to induce chondrogenesis by recombinant adeno-associated virus (rAAV) vector gene transfer of the sex-determining region Y-type high-mobility group box 9 (SOX9) factor upon seeding in three-dimensional-woven poly(ɛ-caprolactone; PCL) scaffolds that provide mechanical properties mimicking those of native articular cartilage. Prolonged, effective SOX9 expression was reported in the constructs for at least 21 days, the longest time point evaluated, leading to enhanced metabolic and chondrogenic activities relative to the control conditions (reporter lacZ gene transfer or absence of vector treatment) but without affecting the proliferative activities in the samples. The application of the rAAV SOX9 vector also prevented undesirable hypertrophic and terminal differentiation in the seeded concentrates. As bone marrow is readily accessible during surgery, such findings reveal the therapeutic potential of providing rAAV-modified marrow concentrates within three-dimensional-woven PCL scaffolds for repair of focal cartilage lesions.

Comparison of Fixation Techniques of 3D-Woven Poly(ϵ-Caprolactone) Scaffolds for Cartilage Repair in a Weightbearing Porcine Large Animal Model.

Objective To test different fixation methods of a 3-dimensionally woven poly(ϵ-caprolactone) (PCL) scaffold within chondral defects of a weightbearing large animal model. Methods Full thickness chondral defects were made in the femoral condyles of 15 adult male Yucatan mini-pigs. Two surgical approaches were compared including total arthrotomy (traditional) and a retinaculum-sparing, minimally invasive surgery (MIS) approach. Following microfracture (MFX), scaffolds were placed without fixation or were fixed with fibrin glue, suture, or subchondral anchor. Experimental endpoints were between 1 and 6 weeks. Micro-computed tomography and histology were used to assess samples. Results The MIS approach was superior as the traditional approach caused medial condyle cartilage wear. One of 13 (7.7%) of scaffolds without fixation, 4 of 11 (36.3%) fibrin scaffolds, 1 of 4 (25%) of sutured scaffolds, and 9 of 9 (100%) of anchor-fixed scaffolds remained in place. Histology demonstrated tissue filling with some overgrowth of PCL scaffolds. Conclusions Of the methods tested, the MIS approach coupled with subchondral anchor fixation provided the best scaffold retention in a mini-pig chondral defect model. This finding has implications for fixation strategies in future animal studies and potential future human use.

Functional outcome measures in a surgical model of hip osteoarthritis in dogs.

BACKGROUND: The hip is one of the most common sites of osteoarthritis in the body, second only to the knee in prevalence. However, current animal models of hip osteoarthritis have not been assessed using many of the functional outcome measures used in orthopaedics, a characteristic that could increase their utility in the evaluation of therapeutic interventions. The canine hip shares similarities with the human hip, and functional outcome measures are well documented in veterinary medicine, providing a baseline for pre-clinical evaluation of therapeutic strategies for the treatment of hip osteoarthritis. The purpose of this study was to evaluate a surgical model of hip osteoarthritis in a large laboratory animal model and to evaluate functional and end-point outcome measures. METHODS: Seven dogs were subjected to partial surgical debridement of cartilage from one femoral head. Pre- and postoperative pain and functional scores, gait analysis, radiographs, accelerometry, goniometry and limb circumference were evaluated through a 20-week recovery period, followed by histological evaluation of cartilage and synovium. RESULTS: Animals developed histological and radiographic evidence of osteoarthritis, which was correlated with measurable functional impairment. For example, Mankin scores in operated limbs were positively correlated to radiographic scores but negatively correlated to range of motion, limb circumference and 20-week peak vertical force. CONCLUSIONS: This study demonstrates that multiple relevant functional outcome measures can be used successfully in a large laboratory animal model of hip osteoarthritis. These measures could be used to evaluate relative efficacy of therapeutic interventions relevant to human clinical care.

Anatomically shaped tissue-engineered cartilage with tunable and inducible anticytokine delivery for biological joint resurfacing.

Biological resurfacing of entire articular surfaces represents an important but challenging strategy for treatment of cartilage degeneration that occurs in osteoarthritis. Not only does this approach require anatomically sized and functional engineered cartilage, but the inflammatory environment within an arthritic joint may also inhibit chondrogenesis and induce degradation of native and engineered cartilage. The goal of this study was to use adult stem cells to engineer anatomically shaped, functional cartilage constructs capable of tunable and inducible expression of antiinflammatory molecules, specifically IL-1 receptor antagonist (IL-1Ra). Large (22-mm-diameter) hemispherical scaffolds were fabricated from 3D woven poly(ε-caprolactone) (PCL) fibers into two different configurations and seeded with human adipose-derived stem cells (ASCs). Doxycycline (dox)-inducible lentiviral vectors containing eGFP or IL-1Ra transgenes were immobilized to the PCL to transduce ASCs upon seeding, and constructs were cultured in chondrogenic conditions for 28 d. Constructs showed biomimetic cartilage properties and uniform tissue growth while maintaining their anatomic shape throughout culture. IL-1Ra-expressing constructs produced nearly 1 µg/mL of IL-1Ra upon controlled induction with dox. Treatment with IL-1 significantly increased matrix metalloprotease activity in the conditioned media of eGFP-expressing constructs but not in IL-1Ra-expressing constructs. Our findings show that advanced textile manufacturing combined with scaffold-mediated gene delivery can be used to tissue engineer large anatomically shaped cartilage constructs that possess controlled delivery of anticytokine therapy. Importantly, these cartilage constructs have the potential to provide mechanical functionality immediately upon implantation, as they will need to replace a majority, if not the entire joint surface to restore function.

Genipin-crosslinked cartilage-derived matrix as a scaffold for human adipose-derived stem cell chondrogenesis.

Autologous cell-based tissue engineering using three-dimensional scaffolds holds much promise for the repair of cartilage defects. Previously, we reported on the development of a porous scaffold derived solely from native articular cartilage, which can induce human adipose-derived stem cells (ASCs) to differentiate into a chondrogenic phenotype without exogenous growth factors. However, this ASC-seeded cartilage-derived matrix (CDM) contracts over time in culture, which may limit certain clinical applications. The present study aimed to investigate the ability of chemical crosslinking using a natural biologic crosslinker, genipin, to prevent scaffold contraction while preserving the chondrogenic potential of CDM. CDM scaffolds were crosslinked in various genipin concentrations, seeded with ASCs, and then cultured for 4 weeks to evaluate the influence of chemical crosslinking on scaffold contraction and ASC chondrogenesis. At the highest crosslinking degree of 89%, most cells failed to attach to the scaffolds and resulted in poor formation of a new extracellular matrix. Scaffolds with a low crosslinking density of 4% experienced cell-mediated contraction similar to our original report on noncrosslinked CDM. Using a 0.05% genipin solution, a crosslinking degree of 50% was achieved, and the ASC-seeded constructs exhibited no significant contraction during the culture period. Moreover, expression of cartilage-specific genes, synthesis, and accumulation of cartilage-related macromolecules and the development of mechanical properties were comparable to the original CDM. These findings support the potential use of a moderately (i.e., approximately one-half of the available lysine or hydroxylysine residues being crosslinked) crosslinked CDM as a contraction-free biomaterial for cartilage tissue engineering.

Composite three-dimensional woven scaffolds with interpenetrating network hydrogels to create functional synthetic articular cartilage.

The development of synthetic biomaterials that possess mechanical properties that mimic those of native tissues remains an important challenge to the field of materials. In particular, articular cartilage is a complex nonlinear, viscoelastic, and anisotropic material that exhibits a very low coefficient of friction, allowing it to withstand millions of cycles of joint loading over decades of wear. Here we show that a three-dimensionally woven fiber scaffold that is infiltrated with an interpenetrating network hydrogel can provide a functional biomaterial that provides the load-bearing and tribological properties of native cartilage. An interpenetrating dual-network "tough-gel" consisting of alginate and polyacrylamide was infused into a porous three-dimensionally woven poly(ε-caprolactone) fiber scaffold, providing a versatile fiber-reinforced composite structure as a potential acellular or cell-based replacement for cartilage repair.

The inhibition by interleukin 1 of MSC chondrogenesis and the development of biomechanical properties in biomimetic 3D woven PCL scaffolds.

Tissue-engineered constructs designed to treat large cartilage defects or osteoarthritic lesions may be exposed to significant mechanical loading as well as an inflammatory environment upon implantation in an injured or diseased joint. We hypothesized that a three-dimensionally (3D) woven poly(ε-caprolactone) (PCL) scaffold seeded with bone marrow-derived mesenchymal stem cells (MSCs) would provide biomimetic mechanical properties in early stages of in vitro culture as the MSCs assembled a functional, cartilaginous extracellular matrix (ECM). We also hypothesized that these properties would be maintained even in the presence of the pro-inflammatory cytokine interleukin-1 (IL-1), which is found at high levels in injured or diseased joints. MSC-seeded 3D woven scaffolds cultured in chondrogenic conditions synthesized a functional ECM rich in collagen and proteoglycan content, reaching an aggregate modulus of ~0.75 MPa within 14 days of culture. However, the presence of pathophysiologically relevant levels of IL-1 limited matrix accumulation and inhibited any increase in mechanical properties over baseline values. On the other hand, the mechanical properties of constructs cultured in chondrogenic conditions for 4 weeks prior to IL-1 exposure were protected from deleterious effects of the cytokine. These findings demonstrate that IL-1 significantly inhibits the chondrogenic development and maturation of MSC-seeded constructs; however, the overall mechanical functionality of the engineered tissue can be preserved through the use of a 3D woven scaffold designed to recreate the mechanical properties of native articular cartilage.

Engineered cartilage using primary chondrocytes cultured in a porous cartilage-derived matrix.

AIM: To investigate the cell growth, matrix accumulation and mechanical properties of neocartilage formed by human or porcine articular chondrocytes on a porous, porcine cartilage-derived matrix (CDM) for use in cartilage tissue engineering. MATERIALS & METHODS: We examined the physical properties, cell infiltration and matrix accumulation in different formulations of CDM and selected a CDM made of homogenized cartilage slurry as an appropriate scaffold for long-term culture of human and porcine articular chondrocytes. RESULTS: The CDM scaffold supported growth and proliferation of both human and porcine chondrocytes. Histology and immunohistochemistry showed abundant cartilage-specific macromolecule deposition at day 28. Human chondrocytes migrated throughout the CDM, showing a relatively homogeneous distribution of new tissue accumulation, whereas porcine chondrocytes tended to form a proteoglycan-rich layer primarily on the surfaces of the scaffold. Human chondrocyte-seeded scaffolds had a significantly lower aggregate modulus and hydraulic permeability at day 28. CONCLUSIONS: These data show that a scaffold derived from native porcine articular cartilage can support neocartilage formation in the absence of exogenous growth factors. The overall characteristics and properties of the constructs depend on factors such as the concentration of CDM used, the porosity of the scaffold, and the species of chondrocytes.

Three-dimensional culture systems to induce chondrogenesis of adipose-derived stem cells.

Stem cells can easily be harvested from adipose tissue in large numbers for use in tissue-engineering approaches for cartilage repair or regeneration. In this chapter, we describe in vitro tissue-engineering models that we have used in our laboratory for the chondrogenic induction of adipose-derived stem cells (ASC). In addition to the proper growth factor environment, chondrogenesis requires cells to be maintained in a rounded morphology in three-dimensional (3D) culture, and thus properties of the biomaterial scaffold also play a critical role in ASC differentiation. Histologic and immunohistologic methods for assessing chondrogenesis are also presented. In general, 10-12 weeks are required to assess ASC chondrogenesis in these model systems.

Multifunctional hybrid three-dimensionally woven scaffolds for cartilage tissue engineering.

The successful replacement of large-scale cartilage defects or osteoarthritic lesions using tissue-engineering approaches will likely require composite biomaterial scaffolds that have biomimetic mechanical properties and can provide cell-instructive cues to control the growth and differentiation of embedded stem or progenitor cells. This study describes a novel method of constructing multifunctional scaffolds for cartilage tissue engineering that can provide both mechanical support and biological stimulation to seeded progenitor cells. 3-D woven PCL scaffolds were infiltrated with a slurry of homogenized CDM of porcine origin, seeded with human ASCs, and cultured for up to 42 d under standard growth conditions. These constructs were compared to scaffolds derived solely from CDM as well as 3-D woven PCL fabric without CDM. While all scaffolds promoted a chondrogenic phenotype of the ASCs, CDM scaffolds showed low compressive and shear moduli and contracted significantly during culture. Fiber-reinforced CDM scaffolds and 3-D woven PCL scaffolds maintained their mechanical properties throughout the culture period, while supporting the accumulation of a cartilaginous extracellular matrix. These findings show that fiber-reinforced hybrid scaffolds can be produced with biomimetic mechanical properties as well as the ability to promote ASC differentiation and chondrogenesis in vitro.

2010 Nicolas Andry Award: Multipotent adult stem cells from adipose tissue for musculoskeletal tissue engineering.

BACKGROUND: Cell-based therapies such as tissue engineering provide promising therapeutic possibilities to enhance the repair or regeneration of damaged or diseased tissues but are dependent on the availability and controlled manipulation of appropriate cell sources. QUESTIONS/PURPOSES: The goal of this study was to test the hypothesis that adult subcutaneous fat contains stem cells with multilineage potential and to determine the influence of specific soluble mediators and biomaterial scaffolds on their differentiation into musculoskeletal phenotypes. METHODS: We reviewed recent studies showing the stem-like characteristics and multipotency of adipose-derived stem cells (ASCs), and their potential application in cell-based therapies in orthopaedics. RESULTS: Under controlled conditions, ASCs show phenotypic characteristics of various cell types, including chondrocytes, osteoblasts, adipocytes, neuronal cells, or muscle cells. In particular, the chondrogenic differentiation of ASCs can be induced by low oxygen tension, growth factors such as bone morphogenetic protein-6 (BMP-6), or biomaterial scaffolds consisting of native tissue matrices derived from cartilage. Finally, focus is given to the development of a functional biomaterial scaffold that can provide ASC-based constructs with mechanical properties similar to native cartilage. CONCLUSIONS: Adipose tissue contains an abundant source of multipotent progenitor cells. These cells show cell surface marker profiles and differentiation characteristics that are similar to but distinct from other adult stem cells, such as bone marrow mesenchymal stem cells (MSCs). CLINICAL RELEVANCE: The availability of an easily accessible and reproducible cell source may greatly facilitate the development of new cell-based therapies for regenerative medicine applications in the musculoskeletal system.