Long-term Evaluation of Meniscal Tissue Formation in 3-dimensional-Printed Scaffolds With Sequential Release of Connective Tissue Growth Factor and TGF-ß3 in an Ovine Model.

BACKGROUND: Artificial meniscal scaffolds are being developed to prevent development of osteoarthritis after meniscectomy. Previously, it was reported that 3-dimensional (3D) anatomic scaffolds loaded with connective tissue growth factor (CTGF) and transforming growth factor ß3 (TGF-ß3) achieved meniscal regeneration in an ovine model. This was a relatively short-term study (3 months postoperative), and outcome analyses did not include magnetic resonance imaging (MRI). PURPOSE: To evaluate long-term outcome of meniscal replacement with growth factor-laden poly-ε-caprolactone (PCL) scaffolds. STUDY DESIGN: Controlled laboratory study. METHODS: Anatomically shaped ovine meniscal scaffolds were fabricated from PCL with a 3D printer based on MRI data. Skeletally mature sheep (N = 34) were randomly allocated to 3 groups: scaffold without growth factor (0-µg group), scaffold with CTGF microspheres (µS) (5 µg) + TGF-ß3 µS (5 µg) (5-µg group), and scaffold with CTGF µS (10 µg) + TGF-ß3 µS (10 µg) (10-µg group). Unilateral medial meniscal replacement was performed. Animals were euthanized at 6 or 12 months. Regenerated meniscus, articular cartilage status, and synovial reaction were evaluated quantitatively with gross inspection, histology, and MRI. Kruskal-Wallis and Dunn tests were used to compare the 3 groups. RESULTS: Remnants of the PCL scaffold were evident in the 6-month specimens and were decreased but still present at 12 months in most animals. There were no significant differences among groups in gross inspection, histology, or MRI for either meniscal regeneration or articular cartilage protection. All experimental groups exhibited articular cartilage degeneration as compared with control (nonoperated). In terms of synovitis, there were no clear differences among groups, suggesting that growth factors did not increase inflammation and fibrosis. MRI revealed that meniscal extrusion was observed in most animals (82.7%). CONCLUSION: Previously, the combination of CTGF and TGF-ß3 was shown to stimulate mesenchymal stem cells into a fibrochondrocyte lineage. CTGF and TGF-ß3 did not aggravate synovitis, suggesting no adverse response to the combination of 3D-printed PCL scaffold combined with CTGF and TGF-ß3. Further work will be required to improve scaffold fixation to avoid meniscal extrusion. CLINICAL RELEVANCE: A significant advantage of this technique is the ability to print custom-fit scaffolds from MRI-generated templates. In addition, average-size menisci could be printed and available for off-the-shelf applications. Based on the 1-year duration of the study, the approach appears to be promising for meniscal regeneration in humans.

Uptake of Drug-Eluting Bioresorbable Vascular Scaffolds in Clinical Practice: An NCDR Registry to Practice Project.

Importance: Physicians have been criticized for having an overly enthusiastic response to new device approvals, especially for novel technologies. However, to our knowledge, the rates of new product adoption and patterns of new device usage in clinical practice have not been well described. Objective: To characterize the patterns of uptake of bioresorbable vascular scaffolds (BVS) within the United States following device approval and to describe changes in response to subsequent releases of data and US Food and Drug Administration (FDA) warnings. Design, Setting, and Participants: This analysis of the uptake of BVS between January 2016 and June 2017 used CathPCI Registry data; all percutaneous coronary intervention (PCI) procedures with an implant of either a BVS or conventional stent were included. Data analysis was performed in October 2017. Exposures: Implant of BVS. Main Outcomes and Measures: The primary outcome was monthly use of BVS in the United States. In addition, the characteristics of patients who received BVS and of hospitals that used BVS were assessed and comparisons of patient characteristics between BVS recipients and patients who were treated contemporaneously with metallic stents were made. Results: Of 682 951 procedures, 471 064 (69.0%) were done in men, 587 301 (86.0%) were among white people, and the mean (SD) age of those undergoing procedures with BVS vs conventional stents was 62.6 (11.4) years vs 65.7 (11.9) years. Of these, 4265 procedures (0.6%) used BVS overall (after FDA approval of BVS). Procedures with implants of BVS occurred among patients with fewer comorbidities and lower-acuity presentations compared with procedures with implants of conventional stents. The patient characteristics for BVS use were not dissimilar to the inclusion criteria of the ABSORB III FDA approval trial, with notable differences based on trial eligibility (eg, excluding patients with myocardial infarctions). The maximum monthly use of BVS was 1.25% of all PCI procedures that occurred 90 days after FDA approval, but with site-to-site variability. Declines in use were observed coincident with the scientific presentation of adverse event data as well as FDA warnings. Conclusions and Relevance: Most US physicians and hospitals were selective in their use of BVS, primarily using them in patients similar to those in the device's FDA approval trial. In addition, declines in use were evident in the subsequent month following the release of data that reported negative outcomes. These results illustrate an example of an appropriate physician response to adverse data updates and FDA warnings.

Reabsorción completa tras implante de múltiples armazones solapados / Complete resorption after implantation of multiple overlapped scaffolds

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Tissue-Engineered Total Meniscus Replacement With a Fiber-Reinforced Scaffold in a 2-Year Ovine Model.

BACKGROUND: Meniscus injuries and associated meniscectomies cause patients long-term pain and discomfort and can lead to joint deterioration. PURPOSE: To evaluate a collagen-hyaluronan sponge reinforced with synthetic resorbable polymer fiber for total meniscus reconstruction in a long-term ovine model. STUDY DESIGN: Controlled laboratory study. METHODS: Eleven skeletally mature sheep were implanted with the total meniscus scaffold. At 2 years, explants were evaluated biologically (radial/circumferential histology, immunofluorescence) and mechanically (compression, tension), and articular surfaces were examined for damage. RESULTS: The fiber-reinforced scaffold induced formation of functional neomeniscus tissue that was intact in 8 of 11 animals. The implant was remodeled into organized circumferentially aligned collagen bundles to resist meniscus hoop stresses. Moreover, type II collagen and proteoglycan deposition near the inner margin suggested a direct response to compressive stresses and confirmed fibrocartilage formation. Cartilage damage was observed, but end-stage (severe) joint deterioration associated with meniscectomy was avoided, even with limitations regarding the ovine surgical procedure and postoperative care. CONCLUSION: A fiber-reinforced total meniscus replacement device induces formation of functional neomeniscus tissue that has the potential to prevent catastrophic joint deterioration associated with meniscectomy. CLINICAL RELEVANCE: An off-the-shelf meniscus device that can be remodeled into functional tissue and thus prevent or delay the onset of osteoarthritis could address a widespread clinical need after meniscus injury.

Therapeutic Effects of the Addition of Platelet-Rich Plasma to Bioimplants and Early Rehabilitation Exercise on Articular Cartilage Repair.

BACKGROUND: Treating articular cartilage lesions is clinically challenging. However, whether the addition of autologous platelet-rich plasma (PRP) to bioimplants along with early rehabilitation exercise provides therapeutic effects and regenerates the osteochondral defect remains uninvestigated. HYPOTHESIS: The addition of PRP to a polylactic-co-glycolic acid (PLGA) scaffold along with continuous passive motion (CPM) in osteochondral defects may offer beneficial in situ microenvironment changes to facilitate hyaline cartilage and subchondral bone tissue repair. STUDY DESIGN: Controlled laboratory study. METHODS: In 26 rabbits, 52 critical osteochondral defects were created in bilateral femoral trochlear grooves. The rabbits were allocated to 1 of the following 3 groups: PRP gel (PG group), PRP + PLGA scaffold (PP group), and PRP + PLGA scaffold + CPM (PPC group). At 4 and 12 weeks after surgery, the specimens were assessed by a macroscopic examination, a histological evaluation with immunohistochemical staining, and micro-computed tomography. RESULTS: The PPC group exhibited the most favorable therapeutic outcomes in terms of hyaline cartilage regeneration. At week 4, the PPC group exhibited significantly higher levels of glycosaminoglycan (GAG) and collagen (COL) II and modest increases in COL I, matrix metalloproteinase-3 (MMP-3), and inflammatory cells with tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). At week 12, the PPC group had significantly higher tissue repair scores, corresponding to a sound articular cartilage surface and chondrocyte and collagen arrangement. This group demonstrated restored hyaline cartilage and mineralized bone volume per tissue volume, which had an integrating structure in the repair site. However, the PG and PP groups exhibited mainly fibrous tissue and fibrocartilage, corresponding to higher expressions of COL I, TNF-α, IL-6, and MMP-3. CONCLUSION: PRP with a PLGA graft along with early CPM exercise is promising for the repair of osteochondral defects in rabbit knee joints. CLINICAL RELEVANCE: This study demonstrates the efficacy of a triad therapy involving the addition of PRP to bioimplants along with early CPM intervention for hyaline cartilage and subchondral regeneration. However, PRP alone (with or without PLGA implants) is limited to osteochondral defect repair without significant regeneration.

Clinical application of a 3D-printed scaffold in chronic wound treatment: a case series.

OBJECTIVE: This case series evaluates the safety and effectiveness of 3D-printed scaffold in chronic wounds. The scaffold is a composite of natural and synthetic materials, and can be prepared in the form of powder or membrane. METHOD: We recruited patients with pressure ulcera (PU) and/or a diabetic foot ulcers (DFU). We used two methods: 3D-printed scaffolds alone, or 3D-printing powder mixed with platelet-rich fibrinogen (PRF). Clinicians and patients were asked to rate the scaffold's ease of application and comfort during use. RESULTS: A total of five patients were recruited; four with a PU and one with a DFU. For the patient treated with the 3D-printed scaffold membrane (n=1), their PU healed in 28 days, and for patients treated with the 3D-printed scaffold powder (n=2), their PUs healed in 54 days. For the patients treated with the 3D-printing powder mixed with PRF (n=2), the patient with a PU healed in 11 days, and the patient with the DFU healed in 14 days. All clinicians rated the 3D-printed scaffold as 'easy' or 'very easy' to use, and patients rated their comfort during wear and at dressing change as 'good' or 'very good'. CONCLUSION: This study demonstrated that 3D-printed scaffold was convenient to use, have the potential to improve wound healing rates, and provided a safe and effective way for treating chronic wounds.

Relevant biological processes for tissue development with stem cells and their mechanistic modeling: A review.

A potential alternative for tissue transplants is tissue engineering, in which the interaction of cells and biomaterials can be optimized. Tissue development in vitro depends on the complex interaction of several biological processes such as extracellular matrix synthesis, vascularization and cell proliferation, adhesion, migration, death, and differentiation. The complexity of an individual phenomenon or of the combination of these processes can be studied with phenomenological modeling techniques. This work reviews the main biological phenomena in tissue development and their mathematical modeling, focusing on mesenchymal stem cell growth in three-dimensional scaffolds.

Electrically Conductive Scaffold to Modulate and Deliver Stem Cells.

Stem cell therapy has emerged as an exciting stroke therapeutic, but the optimal delivery method remains unclear. While the technique of microinjection has been used for decades to deliver stem cells in stroke models, this technique is limited by the lack of ability to manipulate the stem cells prior to injection. This paper details a method of using an electrically conductive polymer scaffold for stem cell delivery. Electrical stimulation of stem cells using a conductive polymer scaffold alters the stem cell's genes involved in cell survival, inflammatory response, and synaptic remodeling. After electrical preconditioning, the stem cells on the scaffold are transplanted intracranially in a distal middle cerebral artery occlusion rat model. This protocol describes a powerful technique to manipulate stem cells via a conductive polymer scaffold and creates a new tool to further develop stem cell-based therapy.

Is There a Role for Internal Bracing and Repair of the Anterior Cruciate Ligament? A Systematic Literature Review.

BACKGROUND: Renewed interest has arisen in arthroscopic anterior cruciate ligament (ACL) repair techniques. HYPOTHESIS: ACL repair with or without some form of internal bracing could lead to good outcomes in a carefully selected subset of patients. STUDY DESIGN: Systematic review. METHODS: An electronic database search was performed to identify 89 papers describing preclinical and clinical studies on the outcome of ACL repair. RESULTS: Proximal ACL tear patterns showed a better healing potential with primary repair than distal or midsubstance tears. Some form of internal bracing increased the success rate of ACL repair. Improvement in the biological characteristics of the repair was obtained by bone marrow access by drilling tunnels or microfracture. Augmentation with platelet-rich plasma was beneficial only in combination with a structural scaffold. Skeletally immature patients had the best outcomes. Acute repair offered improved outcomes with regard to load, stiffness, laxity, and rerupture. CONCLUSION: ACL repair may be a viable option in young patients with acute, proximal ACL tears. The use of internal bracing, biological augmentation, and scaffold tissue may increase the success rate of repair.

The intraoperative use of polydioxanone foil to reduce the risk of sino-orbital fistula formation in orbital exenteration.

BACKGROUND: Orbital exenteration is a radical surgical procedure resulting in deformity. It involves removal of the globe, optic nerve, extra-ocular muscles, orbital fat, lacrimal gland, and peri-osteum. Sino-orbital fistula (SOF) formation is a common documented post-operative complication, usually connecting the orbit and the ethmoid sinus. SOFs can cause leaks of serous fluid, and act as an entry site for pathogens into the orbit leading to socket infection and breakdown. METHODS: This retrospective study analyzed exenterations performed over a 22-year period (1993-2015) at the National Ocular Oncology Service Centre for Scotland. PDS is a crystalline, biodegradable polyether-ester that is strong with good shape-memory and flexibility. Orbital exenterations with and without the use of PDS foil were compared in terms of SOF formation. RESULTS: A total of 30 exenterations were performed during the study period. A total of 29 were analyzed. Choroidal malignant melanoma was the most common indication for performing orbital exenteration (n = 7, 24.14%). The most common post-operative complications seen were SOF (n = 8, 27.59%). A total of 8 out 21 (38.10%) cases not using PDS developed SOFs. By contrast, none of nine patients receiving PDS plates developed SOFs (p = 0.0332). CONCLUSIONS: This is the first study to compare SOF rate in patients undergoing exenteration with and without the use of PDS foil. PDS foil is a safe material, which has effectively reduced the incidence of SOF formation.

Biphasic bioresorbable scaffold (TruFit Plug®) for the treatment of osteochondral lesions of talus: 6- to 8-year follow-up.

BACKGROUND: The ideal treatment of osteochondral lesions of the talus (OLT) is debatable. The TruFit plug has been investigated as a potential treatment method for osteochondral defects. This is a biphasic scaffold designed to stimulate cartilage and subchondral bone formation. The purpose of this retrospective study was to investigate the long-term functional and MRI outcomes of the TruFit Plug for the treatment of OLT. METHODS: Twelve consecutive patients treated from March 2007 to April 2009 for OLT were evaluated. Clinical examination included the American Orthopaedic Foot and Ankle Society (AOFAS) ankle score and the visual analog scale (VAS) for pain. MRI scans were optained pre-treatment and at last follow-up. The Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) score was used to assess cartilage incorporation. RESULTS: Mean follow-up was 7.5 years (range, 6.5-8.7 years). The average age was of 38.6 years (range, 22-57 years). The sex ratio between males and females was 3:1 (9 males, 3 females). The mean AOFAS score improved from a preoperative score of 47.2±10.7 to 84.4±8 (p<0.05). According to the postoperative AOFAS scores 1 case obtained excellent results, 9 were classified as good, and 2 were fair. VAS score improved from a preoperative value of 6.9±1.4 points to 1.2±1.1 points at last follow-up (p<0.05). The MOCART score for cartilage repair tissue on postoperative MRI averaged 61.1 points (range, 25-85 points). CONCLUSIONS: The long-term results suggest that the technique of Trufit Plug for OLT is safe and demonstrates good post-operative scores including improvement of pain and function, with discordant MRI results. However, randomized controlled clinical trials comparing TruFit Plug with an established treatment method are needed to improve synthetic biphasic implants as therapy for osteochondral lesions. LEVEL OF EVIDENCE: Retrospective case series, Level IV.

The mechanisms of late scaffold thrombosis.

Coronary scaffolds have been recently developed to address the long-term limitations of metallic drug eluting stents. Concerns have however been expressed on the safety of these devices, with evidence of both early and late scaffold thrombosis. While early thrombosis has been associated with incomplete scaffold expansion, leading to flow disturbances, blood recirculation, and platelet activation, the pathophysiology of late events remains less understood. Recent cases series have shown that malapposition and scaffold dismantling might play a role in this phenomenon, an observation that further confirms the importance of an accurate implantation. Further, the role of dual antiplatelet therapy, and whether prolonging it may reduce event rates, remains to be elucidated. As well, the role of inflammatory phenomena has been proposed but never demonstrated. This brief review summarizes the current evidence on these phenomena.

Clinical and imaging outcome of osteochondral lesions of the talus treated using autologous matrix-induced chondrogenesis technique with a biomimetic scaffold.

BACKGROUND: The purpose of our study was to assess the clinical and imaging outcome of autologous matrix-induced chondrogenesis (AMIC) technique consisting of microfractures followed by the filling of osteochondral lesions of the talus (OLTs) with a cell-free biphasic collagen-hydroxyapatite osteochondral scaffold (MaioRegen). METHODS: Sixteen patients (eight males, age: 42.6 ± 18.4, range 14-74) with OLT repaired using AMIC technique, with implantation of MaioRegen, were clinically evaluated through the American Orthopedic Foot and Ankle Society Score (AOFAS) and a 10-point Visual Analogue Scale (VAS) pain score after a mean follow-up of 30 ± 16.9 months. The MRI examinations were performed 12 and 24 months after surgery. A paired t-test was applied to compare pre- and post-operative clinical findings (VAS and AOFAS) and Magnetic resonance observation of cartilage repair tissue (MOCART) score changes in the follow-up. To assess the correlation between variation of AOFAS and MOCART scores, the Pearson's correlation coefficient was calculated. RESULTS: No complications after surgery were encountered. From pre-operative to post-operative values, there was a significant (P < 0.001) reduction of mean VAS pain score (6.3 ± 0.9,range: 4-8 and 2.9 ± 1.8,range: 0-6, respectively) and increase of AOFAS score (60.2 ± 7.8,range: 50-74 and 77.4 ± 16.2,range: 50-100, respectively). Among 16 patients, six (37%) were not satisfied at the end of follow-up, six (37%) were moderately satisfied and four (25%) were highly satisfied. The treatment was considered failed in five out of 16 patients (31%). Among them, four (25%) required re-interventions with implantation of ankle prostheses, whereas one patient was treated with a further AMIC technique combined with autologous bone graft and platelet-rich plasma. The mean MOCART score was 41.9 ± 14.6 (25-70) 12 months after surgery and 51.9 ± 11.6 (30-70) after 24 months, with a statistically significant increase (P = 0.012). However, no correlation was seen between AOFAS and MOCART changes (r = 0.215, p = 0.609). CONCLUSION: The high rates of treatment failure encountered in our study using MaioRegen need to be confirmed by larger studies and should induce the scientific community questioning the reliability of this biomimetic scaffold for the treatment of OLTs.

Pyrintegrin Induces Soft Tissue Formation by Transplanted or Endogenous Cells.

Focal adipose deficiency, such as lipoatrophy, lumpectomy or facial trauma, is a formidable challenge in reconstructive medicine, and yet scarcely investigated in experimental studies. Here, we report that Pyrintegrin (Ptn), a 2,4-disubstituted pyrimidine known to promote embryonic stem cells survival, is robustly adipogenic and induces postnatal adipose tissue formation in vivo of transplanted adipose stem/progenitor cells (ASCs) and recruited endogenous cells. In vitro, Ptn stimulated human adipose tissue derived ASCs to differentiate into lipid-laden adipocytes by upregulating peroxisome proliferator-activated receptor (PPARγ) and CCAAT/enhancer-binding protein-α (C/EBPα), with differentiated cells increasingly secreting adiponectin, leptin, glycerol and total triglycerides. Ptn-primed human ASCs seeded in 3D-bioprinted biomaterial scaffolds yielded newly formed adipose tissue that expressed human PPARγ, when transplanted into the dorsum of athymic mice. Remarkably, Ptn-adsorbed 3D scaffolds implanted in the inguinal fat pad had enhanced adipose tissue formation, suggesting Ptn's ability to induce in situ adipogenesis of endogenous cells. Ptn promoted adipogenesis by upregulating PPARγ and C/EBPα not only in adipogenesis induction medium, but also in chemically defined medium specifically for osteogenesis, and concurrently attenuated Runx2 and Osx via BMP-mediated SMAD1/5 phosphorylation. These findings suggest Ptn's novel role as an adipogenesis inducer with a therapeutic potential in soft tissue reconstruction and augmentation.

Current practices of Asia-Pacific cardiologists in the utilization of bioresorbable scaffolds.

BACKGROUND & AIMS: Although Absorb Bioresorbable Vascular Scaffolds (A-BVS) are routinely used in the Asia-Pacific, there is little information on patient selection or deployment technique here. This document investigates the experiences of leading interventional cardiologists from the Asia-Pacific region with a focus on patient characteristics, deployment techniques and management. METHODS AND RESULTS: A detailed questionnaire was distributed to 28 highly-experienced interventional cardiologists ('Authors') from 13 Asia-Pacific countries. The results were discussed at a meeting on patient selection, technical consideration, deployment practices and patient management. Potential patient benefits of Absorb compared to metallic DES, the learning curve for patient selection and preparation, device deployment, and subsequent patient management approaches are presented. CONCLUSIONS: Current practices are derived from guidelines optimized for European patients. Differences in approach exist in the Asia-Pacific context, including limited access to imaging and frequency of occurrence of complex lesions. Nevertheless, the use of the Absorb BVS ('Absorb') in certain Asia-Pacific countries has flourished and practices here are continuing to mature.

Twelve-Month Outcomes With a Bioresorbable Everolimus-Eluting Scaffold: Results of the ESHC-BVS Registry at Two Australian Centers.

BACKGROUND: The Absorb bioresorbable vascular scaffold (BVS; Abbott Vascular) is a relatively new type of coronary stent designed to provide temporary vessel scaffolding following percutaneous coronary intervention. International use of the device has grown despite a relative paucity of clinical data regarding the performance of the device and the optimal strategy for its use. We report 12-month clinical data on the Absorb BVS from a real-world registry in order to contribute to the overall understanding of the BVS device. METHODS AND RESULTS: Absorb BVS implantation was attempted in 152 lesions in 100 patients at two Sydney hospitals, as part of the prospective ESHC-BVS registry. Patients selected harbored a range of complex lesions as encountered in real-world practice. Type-C lesions made up 37% of all lesions treated, with 64% of these being long lesions (>20 mm). Device success was achieved in 98.8% of cases. Predilation was performed in all scaffolds and postdilation was performed in 95% of scaffolds to a mean of 19.6 ± 4.6 atm. Twelve-month follow-up data were available for 99% of patients. At 12 months, the cumulative incidence of target-lesion revascularization was 4%, while the incidence of myocardial infarction was 2% and the incidence of scaffold thrombosis was 1%. There were no deaths in the follow-up period. CONCLUSION: In a cohort including complex lesions encountered in real-world practice, the Absorb BVS was associated with low rates of target-lesion revascularization, myocardial infarction, and scaffold thrombosis at 12 months when used with a strategy of meticulous lesion preparation, routine postdilation, and 12 months of dual-antiplatelet therapy.