Surrogate End Points for Overall Survival in Metastatic, Locally Advanced, or Unresectable Pancreatic Cancer: A Systematic Review and Meta-Analysis of 24 Randomized Controlled Trials.

BACKGROUND: Overall survival (OS) has traditionally been the primary end point in studies evaluating the clinical benefit of first-line chemotherapy in metastatic, locally advanced, or unresectable pancreatic cancer (MLAUPC). Given the prolonged follow-up assessment required to obtain OS and its potential to be confounded by second-line treatments, this study sought to determine whether progression-free survival (PFS), response rate (RR), or disease control rate (DCR) can serve as a reliable surrogate for OS. METHODS: A systematic review and meta-analysis was performed including all phase 3 clinical trials for MLAUPC, with gemcitabine as the control arm of the trial. The hazard ratios (HRs) for OS and PFS and odds ratios (ORs) for RR and DCR were recorded. A weighted Pearson correlation coefficient was estimated for the association between OS and the other outcomes. The primary analysis used a random effects weighting model, whereas the secondary analyses used a fixed effects- or sample size-weighted approach. RESULTS: For the study, 24 randomized controlled trials were identified. The Pearson correlation coefficient between OS and PFS was 0.86 (95% confidence interval [CI] 0.67-0.94; p < 0.001). Sensitivity analysis of the studies with little to no crossover further showed a correlation coefficient of 0.91 (95% CI 0.76-0.97; p < 0.001). The correlation coefficient between OS and RR was 0.45 (95% CI 0.07-0.72; p = 0.02) and between OS and DCR was 0.74 (95% CI 0.38-0.90; p < 0.001). CONCLUSIONS: First-line chemotherapy trials for MLAUPC show a robust correlation between OS and PFS, affirming its role as a surrogate of OS.

A copper sulfate and hydroxylysine treatment regimen for enhancing collagen cross-linking and biomechanical properties in engineered neocartilage.

The objective of this study was to improve the biomechanical properties of engineered neotissues through promoting the development of collagen cross-links. It was hypothesized that supplementing medium with copper sulfate and the amino acid hydroxylysine would enhance the activity of lysyl oxidase enzyme to form collagen cross-links, increasing the strength and integrity of the neotissue. Neocartilage constructs were generated using a scaffoldless, self-assembling process and treated with copper sulfate and hydroxylysine, either alone or in combination, following a 2-factor, full-factorial study design. Following a 6-wk culture period, the biomechanical and biochemical properties of the constructs were measured. Results found copper sulfate to significantly increase pyridinoline (PYR) cross-links in all copper sulfate-containing groups over controls. When copper sulfate and hydroxylysine were combined, the result was synergistic, with a 10-fold increase in PYR content over controls. This increase in PYR cross-links manifested in a 3.3-fold significant increase in the tensile properties of the copper sulfate + hydroxylysine group. In addition, an 123% increase over control values was detected in the copper sulfate group in terms of the aggregate modulus. These data elucidate the role of copper sulfate and hydroxylysine toward improving the biomechanical properties of neotissues through collagen cross-linking enhancement.

Fortifying the Bone-Implant Interface Part 1: An In Vitro Evaluation of 3D-Printed and TPS Porous Surfaces.

BACKGROUND: An aging society and concomitant rise in the incidence of impaired bone health have led to the need for advanced osteoconductive spinal implant surfaces that promote greater biological fixation (e.g. for interbody fusion cages, sacroiliac joint fusion implants, and artificial disc replacements). Additive manufacturing, i.e. 3D-printing, may improve bone integration by generating biomimetic spinal implant surfaces that mimic bone morphology. Such surfaces may foster an enhanced cellular response compared to traditional implant surfacing processes. METHODS: This study investigated the response of human osteoblasts to additive manufactured (AM) trabecular-like titanium implant surfaces compared to traditionally machined base material with titanium plasma spray (TPS) coated surfaces, with and without a nanocrystalline hydroxyapatite (HA) coating. For TPS-coated discs, wrought Ti6Al4V ELI was machined and TPS-coating was applied. For AM discs, Ti6Al4V ELI powder was 3D-printed to form a solid base and trabecular-like porous surface. The HA-coating was applied via a precipitation dip-spin method. Surface porosity, pore size, thickness, and hydrophilicity were characterized. Initial cell attachment, proliferation, alkaline phosphatase (ALP) activity, and calcium production of hFOB cells (n=5 per group) were measured. RESULTS: Cells on AM discs exhibited expedited proliferative activity. While there were no differences in mean ALP expression and calcium production between TPS and AM discs, calcium production on the AM discs trended 48% higher than on TPS discs (p=0.07). Overall, HA-coating did not further enhance results compared to uncoated TPS and AM discs. CONCLUSIONS: Results demonstrate that additive manufacturing allows for controlled trabecular-like surfaces that promote earlier cell proliferation and trends toward higher calcium production than TPS coating. Results further showed that nanocrystalline HA may not provide an advantage on porous titanium surfaces. CLINICAL RELEVANCE: Additive manufactured porous titanium surfaces may induce a more osteogenic environment compared to traditional TPS, and thus present as an attractive alternative to TPS-coating for orthopedic spinal implants.

Fortifying the Bone-Implant Interface Part 2: An In Vivo Evaluation of 3D-Printed and TPS-Coated Triangular Implants.

BACKGROUND: Minimally invasive surgical fusion of the sacroiliac (SI) joint using machined solid triangular titanium plasma spray (TPS) coated implants has demonstrated positive clinical outcomes in SI joint pain patients. Additive manufactured (AM), i.e. 3D-printed, fenestrated triangular titanium implants with porous surfaces and bioactive agents, such as nanocrystalline hydroxyapatite (HA) or autograft, may further optimize bony fixation and subsequent biomechanical stability. METHODS: A bilateral ovine distal femoral defect model was used to evaluate the cancellous bone-implant interfaces of TPS-coated and AM implants. Four implant groups (n=6/group/time-point) were included: 1)TPS-coated, 2)AM, 3)AM+HA, and 4)AM+Autograft. The bone-implant interfaces of 6- and 12-week specimens were investigated via radiographic, biomechanical, and histomorphometric methods. RESULTS: Imaging showed peri-implant bone formation around all implants. Push-out testing demonstrated forces greater than 2500 N, with no significant differences among groups. While TPS implants failed primarily at the bone-implant interface, AM groups failed within bone ~2-3mm away from implant surfaces. All implants exhibited bone ongrowth, with no significant differences among groups. AM implants had significantly more bone ingrowth into their porous surfaces than TPS-coated implants (p<0.0001). Of the three AM groups, AM+Auto implants had the greatest bone ingrowth into the porous surface and through their core (p<0.002). CONCLUSIONS: Both TPS and AM implants exhibited substantial bone ongrowth and ingrowth, with additional bone through growth into the AM implants' core. Overall, AM implants experienced significantly more bone infiltration compared to TPS implants. While HA-coating did not further enhance results, the addition of autograft fostered greater osteointegration for AM implants. CLINICAL RELEVANCE: Additive manufactured implants with a porous surface provide a highly interconnected porous surface that has comparatively greater surface area for bony integration. Results suggest this may prove advantageous toward promoting enhanced biomechanical stability compared to TPS-coated implants for SI joint fusion procedures.

Utility of Intraoperative Neuromonitoring during Minimally Invasive Fusion of the Sacroiliac Joint.

Study Design. Retrospective case series. Objective. To document the clinical utility of intraoperative neuromonitoring during minimally invasive surgical sacroiliac joint fusion for patients diagnosed with sacroiliac joint dysfunction (as a direct result of sacroiliac joint disruptions or degenerative sacroiliitis) and determine stimulated electromyography thresholds reflective of favorable implant position. Summary of Background Data. Intraoperative neuromonitoring is a well-accepted adjunct to minimally invasive pedicle screw placement. The utility of intraoperative neuromonitoring during minimally invasive surgical sacroiliac joint fusion using a series of triangular, titanium porous plasma coated implants has not been evaluated. Methods. A medical chart review of consecutive patients treated with minimally invasive surgical sacroiliac joint fusion was undertaken at a single center. Baseline patient demographics and medical history, intraoperative electromyography thresholds, and perioperative adverse events were collected after obtaining IRB approval. Results. 111 implants were placed in 37 patients. Sensitivity of EMG was 80% and specificity was 97%. Intraoperative neuromonitoring potentially avoided neurologic sequelae as a result of improper positioning in 7% of implants. Conclusions. The results of this study suggest that intraoperative neuromonitoring may be a useful adjunct to minimally invasive surgical sacroiliac joint fusion in avoiding nerve injury during implant placement.

Combined use of chondroitinase-ABC, TGF-ß1, and collagen crosslinking agent lysyl oxidase to engineer functional neotissues for fibrocartilage repair.

Patients suffering from damaged or diseased fibrocartilages currently have no effective long-term treatment options. Despite their potential, engineered tissues suffer from inferior biomechanical integrity and an inability to integrate in vivo. The present study identifies a treatment regimen (including the biophysical agent chondroitinase-ABC, the biochemical agent TGF-ß1, and the collagen crosslinking agent lysyl oxidase) to prime highly cellularized, scaffold-free neofibrocartilage implants, effecting continued improvement in vivo. We show these agents drive in vitro neofibrocartilage matrix maturation toward synergistically enhanced Young's modulus and ultimate tensile strength values, which were increased 245% and 186%, respectively, over controls. Furthermore, an in vitro fibrocartilage defect model found this treatment regimen to significantly increase the integration tensile properties between treated neofibrocartilage and native tissue. Through translating this technology to an in vivo fibrocartilage defect model, our results indicate, for the first time, that a pre-treatment can prime neofibrocartilage for significantly enhanced integration potential in vivo, with interfacial tensile stiffness and strength increasing by 730% and 745%, respectively, compared to integration values achieved in vitro. Our results suggest that specifically targeting collagen assembly and organization is a powerful means to augment overall neotissue mechanics and integration potential toward improved clinical feasibility.

Passive strain-induced matrix synthesis and organization in shape-specific, cartilaginous neotissues.

Tissue-engineered musculoskeletal soft tissues typically lack the appropriate mechanical robustness of their native counterparts, hindering their clinical applicability. With structure and function being intimately linked, efforts to capture the anatomical shape and matrix organization of native tissues are imperative to engineer functionally robust and anisotropic tissues capable of withstanding the biomechanically complex in vivo joint environment. The present study sought to tailor the use of passive axial compressive loading to drive matrix synthesis and reorganization within self-assembled, shape-specific fibrocartilaginous constructs, with the goal of developing functionally anisotropic neotissues. Specifically, shape-specific fibrocartilaginous neotissues were subjected to 0, 0.01, 0.05, or 0.1 N axial loads early during tissue culture. Results found the 0.1-N load to significantly increase both collagen and glycosaminoglycan synthesis by 27% and 67%, respectively, and to concurrently reorganize the matrix by promoting greater matrix alignment, compaction, and collagen crosslinking compared with all other loading levels. These structural enhancements translated into improved functional properties, with the 0.1-N load significantly increasing both the relaxation modulus and Young's modulus by 96% and 255%, respectively, over controls. Finite element analysis further revealed the 0.1-N uniaxial load to induce multiaxial tensile and compressive strain gradients within the shape-specific neotissues, with maxima of 10.1%, 18.3%, and -21.8% in the XX-, YY-, and ZZ-directions, respectively. This indicates that strains created in different directions in response to a single axis load drove the observed anisotropic functional properties. Together, results of this study suggest that strain thresholds exist within each axis to promote matrix synthesis, alignment, and compaction within the shape-specific neotissues. Tailoring of passive axial loading, thus, presents as a simple, yet effective way to drive in vitro matrix development in shape-specific neotissues toward more closely achieving native structural and functional properties.

A chondroitinase-ABC and TGF-ß1 treatment regimen for enhancing the mechanical properties of tissue-engineered fibrocartilage.

The development of functionally equivalent fibrocartilage remains elusive despite efforts to engineer tissues such as knee meniscus, intervertebral disc and temporomandibular joint disc. Attempts to engineer these structures often fail to create tissues with mechanical properties on a par with native tissue, resulting in constructs unsuitable for clinical applications. The objective of this study was to engineer a spectrum of biomimetic fibrocartilages representative of the distinct functional properties found in native tissues. Using the self-assembly process, different co-cultures of meniscus cells and articular chondrocytes were seeded into agarose wells and treated with the catabolic agent chondroitinase-ABC (C-ABC) and the anabolic agent transforming growth factor-ß1 (TGF-ß1) via a two-factor (cell ratio and bioactive treatment), full factorial study design. Application of both C-ABC and TGF-ß1 resulted in a beneficial or positive increase in the collagen content of treated constructs compared to controls. Significant increases in both the collagen density and fiber diameter were also seen with this treatment, increasing these values by 32 and 15%, respectively, over control values. Mechanical testing found the combined bioactive treatment to synergistically increase the Young's modulus and ultimate tensile strength of the engineered fibrocartilages compared to controls, with values reaching the lower spectrum of those found in native tissues. Together, these data demonstrate that C-ABC and TGF-ß1 interact to develop a denser collagen matrix better able to withstand tensile loading. This study highlights a way to optimize the tensile properties of engineered fibrocartilage using a biochemical and a biophysical agent together to create distinct fibrocartilages with functional properties mimicking those of native tissue.

Engineering functional anisotropy in fibrocartilage neotissues.

The knee meniscus, intervertebral disc, and temporomandibular joint (TMJ) disc all possess complex geometric shapes and anisotropic matrix organization. While these characteristics are imperative for proper tissue function, they are seldom recapitulated following injury or disease. Thus, this study's objective was to engineer fibrocartilages that capture both gross and molecular structural features of native tissues. Self-assembled TMJ discs were selected as the model system, as the disc exhibits a unique biconcave shape and functional anisotropy. To drive anisotropy, 50:50 co-cultures of meniscus cells and articular chondrocytes were grown in biconcave, TMJ-shaped molds and treated with two exogenous stimuli: biomechanical (BM) stimulation via passive axial compression and bioactive agent (BA) stimulation via chondroitinase-ABC and transforming growth factor-ß1. BM + BA synergistically increased Col/WW, Young's modulus, and ultimate tensile strength 5.8-fold, 14.7-fold, and 13.8-fold that of controls, respectively; it also promoted collagen fibril alignment akin to native tissue. Finite element analysis found BM stimulation to create direction-dependent strains within the neotissue, suggesting shape plays an essential role toward driving in vitro anisotropic neotissue development. Methods used in this study offer insight on the ability to achieve physiologic anisotropy in biomaterials through the strategic application of spatial, biomechanical, and biochemical cues.

Temporomandibular disorders: a review of etiology, clinical management, and tissue engineering strategies.

Temporomandibular disorders (TMD) are a class of degenerative musculoskeletal conditions associated with morphologic and functional deformities that affect up to 25% of the population, but their etiology and progression are poorly understood and, as a result, treatment options are limited. In up to 70% of cases, TMD are accompanied by malpositioning of the temporomandibular joint (TMJ) disc, termed "internal derangement." Although the onset is not well characterized, correlations between internal derangement and osteoarthritic change have been identified. Because of the complex and unique nature of each TMD case, diagnosis requires patient-specific analysis accompanied by various diagnostic modalities. Likewise, treatment requires customized plans to address the specific characteristics of each patient's disease. In the mechanically demanding and biochemically active environment of the TMJ, therapeutic approaches that can restore joint functionality while responding to changes in the joint have become a necessity. One such approach, tissue engineering, which may be capable of integration and adaptation in the TMJ, carries significant potential for the development of repair and replacement tissues. The following review presents a synopsis of etiology, current treatment methods, and the future of tissue engineering for repairing and/or replacing diseased joint components, specifically the mandibular condyle and TMJ disc. An analysis of native tissue characterization to assist clinicians in identifying tissue engineering objectives and validation metrics for restoring healthy and functional structures of the TMJ is followed by a discussion of current trends in tissue engineering.