Mechanically superior matrices promote osteointegration and regeneration of anterior cruciate ligament tissue in rabbits

The gold standard treatment for anterior cruciate ligament (ACL) reconstruction is the use of tendon autografts and allografts. Limiting factors for this treatment include donor site morbidity, potential disease transmission, and variable graft quality. To address these limitations, we previously developed an off-the-shelf alternative, a poly(l-lactic) acid (PLLA) bioengineered ACL matrix, and demonstrated its feasibility to regenerate ACL tissue. This study aims to 1) accelerate the rate of regeneration using the bioengineered ACL matrix by supplementation with bone marrow aspirate concentrate (BMAC) and growth factors (BMP-2, FGF-2, and FGF-8) and 2) increase matrix strength retention. Histological evaluation showed robust tissue regeneration in all groups. The presence of cuboidal cells reminiscent of ACL fibroblasts and chondrocytes surrounded by an extracellular matrix rich in anionic macromolecules was up-regulated in the BMAC group. This was not observed in previous studies and is indicative of enhanced regeneration. Additionally, intraarticular treatment with FGF-2 and FGF-8 was found to suppress joint inflammation. To increase matrix strength retention, we incorporated nondegradable fibers, polyethylene terephthalate (PET), into the PLLA bioengineered ACL matrix to fabricate a “tiger graft.” The tiger graft demonstrated the greatest peak loads among the experimental groups and the highest to date in a rabbit model. Moreover, the tiger graft showed superior osteointegration, making it an ideal bioengineered ACL matrix. The results of this study illustrate the beneficial effect bioactive factors and PET incorporation have on ACL regeneration and signal a promising step toward the clinical translation of a functional bioengineered ACL matrix.

The goal of developing a bioengineered anterior cruciate ligament (ACL) matrix is to provide an off-the-shelf product that is functionally superior to autografts and allografts currently used for ACL reconstruction surgeries. There is clear need for advancement in this area as 30% of young active patients reinjure their ACL after surgery (1). Furthermore, athletes in the National Basketball Association and National Football League have a return-to-sport time after ACL reconstruction of 11.6 and 10.8 mo, respectively (2, 3). This lengthy period of rehabilitation has spurred interest in bioengineered ACL matrices that can accelerate and enhance ACL regeneration, so that all patients can return to their preinjury performance level faster.Our group previously fabricated a poly(l-lactic) acid (PLLA) bioengineered ACL matrix and evaluated its performance in rabbit ACL reconstruction models (4–7). The bioengineered ACL matrix resulted in excellent tissue regeneration, while experiencing a 41 to 66% rupture rate in vivo (4, 5). The cause of these ruptures was likely due to the interplay between the rate of tissue regeneration and matrix fatigue. Thus, this study aims to 1) accelerate ACL regeneration by supplementing the bioengineered ACL matrix with bone marrow aspirate concentrate (BMAC) and growth factors (bone morphogenetic protein 2 [BMP-2], fibroblast growth factor 2 [FGF-2], and FGF-8); and 2) increase the strength retention of the bioengineered ACL matrix by incorporating nondegradable polyethylene terephthalate (PET) yarns.BMAC is a promising translational stem cell therapy as it can be harvested and applied during surgery and is not regulated by the US Food and Drug Administration (FDA) (8, 9). The ability of BMAC to enhance the repair of damaged rotator cuff (10) and meniscus (11) tissues has been demonstrated in rabbit models. Thus, we hypothesized that the application of BMAC would serve as a source of progenitor cells and bioactive factors that would accelerate ACL regeneration. This report evaluates the feasibility of obtaining BMAC in a rabbit ACL reconstruction model and its regenerative potential.Growth factors have been widely investigated to accelerate bone and ligament regeneration through the proliferation and differentiation of progenitor cells (12). FGFs have been shown to stimulate the proliferation of cells and enhance tissue healing. In particular, FGF-2 has been shown to accelerate ligament healing (13), and a member of the FGF-8 subfamily has been shown to stimulate cartilage healing in a clinical study (14). Furthermore, the synergistic application of FGF-2 and FGF-8 induced dedifferentiation of mature cells in axolotls (15). Given the evidence supporting the proregenerative qualities of FGF-2 and FGF-8, we chose to apply FGF-2 and FGF-8 simultaneously in the intraarticular space. We hypothesized that the combinatorial application of FGF-2 and FGF-8 would accelerate ligamentization of the bioengineered ACL matrix by promoting the proliferation of progenitor cells and dedifferentiation of mature cells in the synovial environment.To accelerate bone regeneration, we utilized bone morphogenetic protein 2 (BMP-2), which is approved by the US FDA for a range of lumbar spinal fusion procedures and has been shown in ACL reconstruction models to enhance osteointegration of tendon grafts (16–18). In our previous study, we demonstrated that BMP-2 saline injections could enhance osteoid seam width and reduce bone tunnel cross-sectional area, a sign of bone regeneration (5). However, the effect was limited, likely due to the lack of a drug carrier. In this study, we hypothesized that the addition of a drug delivery carrier, fibrin glue (19–22), would potentiate the effect of BMP-2 and promote bone formation (23).The first iteration of the bioengineered ACL matrix, termed the “L-C ligament,” was completely biodegradable and composed of only PLLA yarns (4). The high rupture rate found in our previous study motivated us to modify the material composition of the bioengineered ACL matrix to reduce its mechanical fatigue rate. A compelling polymer to reduce fatigue rate is PET, a biocompatible nondegradable polymer with high tensile strength that has previously been utilized for orthopedic applications (24). To date, no study has investigated the use of a composite PLLA and PET bioengineered ACL matrix for ACL reconstruction. Following the patented design by Laurencin and colleagues (25), a composite bioengineered ACL matrix, termed the “tiger graft,” composed of 20 PLLA yarns and 4 PET yarns, was fabricated. The PLLA facilitates a greater volume of tissue regeneration as it gradually degrades, while the PET bolsters the mechanical strength of the matrix during the early phases of healing. We hypothesized that the tiger graft would have increased mechanical strength retention over the implantation period.The overall goal of this study was to accelerate ACL regeneration of a bioengineered ACL matrix by supplementation with BMAC and growth factors (BMP-2, FGF-2, and FGF-8) and by modulating the material composition of the matrix (Fig. 1). We evaluated the ligamentization and osteointegration of the bioengineered ACL matrices histologically. Microcomputed tomography (µCT) was performed to evaluate bone tunnel regeneration. The inflammatory and remodeling state of the synovial fluid was evaluated using an enzyme-linked immunosorbent assay (ELISA). Finally, biomechanical testing was conducted to determine the strength retention of the bioengineered ACL matrices.Open in a separate windowFig. 1.Fabrication of the bioengineered ACL matrix and implantation in a rabbit ACL reconstruction model. (A) Depiction of the braiding machine used to fabricate the bioengineered ACL matrices and the resulting biphasic structure of the matrix. Each matrix was composed of 24 yarns. (B) For the L-C ligament, 24 yarns of PLLA were braided together. For the tiger graft, 20 yarns of PLLA and 4 yarns of PET were braided together. Experimental groups were evaluated at 12 wk, and the L-C ligament (control) was further evaluated at 24 wk. (C) View of implanted bioengineered ACL matrix at the time of surgery (Left) and the application of fibrin glue (Right). BMAC or growth factors were mixed with fibrin glue for the experimental groups. (D) Representative image demonstrating the implantation of a fibrin gel in the tibial bone tunnel (Left, blue arrow) and subsequent fixation of a titanium suture button (Right).     

Evaluation of acute/late toxicity and local recurrence in T1–T2 glottic carcinoma treated with accelerated hypofractionated 3D-conformal external beam radiotherapy (3D-CRT)

Background

The aim of the study was to evaluate the efficacy, as well as the acute and late toxicity of an accelerated hypofractionated 3DCRT schedule as radical treatment in patients with organ confined glottic cancer cT1-2N0.

Patients and methods.

Between June of 2004 and September 2010, 47 retrospectively selected patients (29 males, 18 females) diagnosed with organ confined T1 or T2 glottic cancer, were treated with external 3DCRT in an accelerated hypofractionation schedule. The median age was 70 years. A dose of 64.4 Gy in 28 daily fractions was prescribed. The primary study endpoints were to assess the acute and late effects of radiation toxicity, according to the EORTC/ RTOG scale, as well as the therapeutic impact of this schedule in terms of local recurrence.

Results

The median follow up was 36 months. At the end of radiotherapy, grade I, II and III acute toxicity was observed in 34, 9 and4 patients, respectively. Late grade I and II toxicity was observed in 25 and in 8 patients respectively. Only two local recurrences were observed, 15 and 24 months post 3DCRT respectively.

Conclusions

Our radiotherapy schedule achieves a high locoregional control rate with the advantage of voice preservation. The proposed hypofractionated schedule can be recommended as a standard radiotherapy treatment, since these results are comparable with those of conventional fractionation schedules.     

Ureteral endometriosis

PURPOSE: This review discusses the pathophysiology, presentation, and different minimally invasive medical and surgical treatment options for ureteral endometriosis. MATERIALS AND METHODS: A comprehensive literature review of reports on the diagnosis and management of ureteral endometriosis was performed using MEDLINE. RESULTS: Ureteral endometriosis is a rare disease. Most cases present with silent obstruction, as opposed to cyclical hematuria. The diagnosis of ureteral endometriosis requires a high index of suspicion. A variety of diagnostic tests can help identify the extent of disease and the degree of renal function on the side of ureteral involvement. CONCLUSIONS: Ureteral endometriosis can be treated with hormones or surgical intervention. While surgery is reserved for hormone refractory cases and obstruction associated with extensive scarring, the majority of cases can be managed with hormones only. A combination of hormones and surgery is also effective. Surveillance for obstructive uropathy with periodic noninvasive monitoring of kidney function is currently recommended for all patients with endometriosis.     

Embolization as an Alternative Treatment of Insulinoma in a Patient with Multiple Endocrine Neoplasia Type 1 Syndrome

Insulinoma is a rare neuroendocrine tumor, most commonly originating from the pancreas, which is either sporadic or familial as a component of multiple endocrine neoplasia type 1 syndrome (MEN1). It is characterized by increased insulin secretion leading to hypoglycemia. Surgical removal is considered the treatment of choice, with limited side effects and relatively low morbidity and mortality, both being improved by the laparoscopic procedure. We present the case of a 30-year-old patient with MEN1 and recurrent insulinoma with severe hypoglycemic episodes who could not be surgically treated due to the adherence of the tumor to large blood vessels and to prior multiple surgical operations. He was treated by repeated embolization using spherical polyvinyl alcohol particles, resulting in shrinkage of the tumor, improvement of the frequency and severity of the hypoglycemic episodes, and better quality of life.     

Synchronous rectal and colon cancer caused by familial polyposis coli during pregnancy

The management of colon and rectal cancer during pregnancy is controversial and challenging. Rectal or colon cancer during pregnancy is a very rare event. A 29-year-old woman, pregnant with her second child, was diagnosed with rectal cancer causing bowel obstruction and synchronous colon cancer during the 27th week of gestation. Both cancers occurred as a result of familial polyposis. This is the first case of synchronous rectal and colon cancer caused by familial polyposis during pregnancy reported in the published literature. We discuss the therapeutic interventions and the surgical management of the cancer in relation to the gestation.     

Knowledge of the Therapeutic Goals of Diabetes Care among Patients with Type 2 Diabetes at a Tertiary Hospital in Ethiopia

BackgroundA comprehensive cardiovascular risk control reduces diabetes-associated complications but achieving the triplet goals (blood glucose, blood pressure (BP), and low-density lipoprotein (LDL-C)) remains a clinical challenge. Patients'' knowledge of these diabetes therapeutic goals has been shown to improve glycemic control. However, this is not well studied in Ethiopia.MethodsA cross-sectional study was conducted from March to June 2020 in Tikur Anbessa Specialized Hospital among randomly selected 419 patients with type 2 diabetes. Data was collected using a pretested, structured questionnaire. A multivariable binary logistic regression was fitted to identify determinants of knowledge.ResultsThe mean age (±SD) of study participants was 57.4 (±10.8) years and the median duration (IQR) of diabetes was 12 (7, 20) years. A quarter of them achieved fasting glycemic control, a fifth of them attained the A1c goal and only 3% achieved the triple targets. Patients who reported knowing their target goals for BP, fasting blood sugar (FBS), A1C, and LDL-C were 79.5, 77.3, 11.7, and 7.2% respectively. The factors associated with knowledge of the therapeutic goals were longer diabetes duration, increased household income, age, being divorced as compared to married, having no formal education, and primary education.ConclusionThe majority of participants knew their BP and FBS targets while only a minority understood their A1c and LDL-C targets. It highlighted the need for the provision of patient-centered diabetes education to improve knowledge of the therapeutic targets.     

Arthroscopic meniscal repair evaluated with repeat arthroscopy

Arthroscopic meniscal repair is a technically feasible approach to the treatment of meniscal tears in young active individuals. To evaluate this premise, we repaired 29 minisci in 27 patients and then arthroscoped their knees 3 months later. Repairs were limited to displaceable longitudinal tears. In 16 patients ligaments were intact. Eleven patients were anterior cruciate ligament deficient, six of whom underwent concomitant ACL reconstructions. In two patients, bicompartmental tears were encountered. Under arthroscopic control, using curved cannulae, horizontal mattress sutures of absorbable monofilament were placed across the tear, out through the capsule, and tied over the fascia, deep to the skin. No arthrotomies were performed, and all portions of the menisci could be reached with this method. Twenty-four of 29 repairs healed completely; 5 healed partially (30 to 50% healing). Four of the five failed repairs occurred in unstable anterior cruciate ligament deficient knees.     

Anterior and anterior-inferior shoulder instability: Treatment by glenoid labrum reconstruction and a modified capsular shift procedure

An anterior glenoid labrum reconstruction in conjunction with a modified anterior-inferior capsular shift is described and was performed in 64 patients (69 shoulders) with traumatic anterior or anterior-inferior glenohumeral instability. Sixty-three operations were performed for recurrent dislocation and six for recurrent subluxation. The patients in this study were extremely active in sports, with the majority of Tegner ratings exceeding 7.0. Fifty-six patients with 61 operated shoulders were available for clinical follow-up at an average of 36 months (range 28 to 78 months). With rating scales from the American Shoulder and Elbow Surgeons, pain improved from an average of 3.1 to an average of 4.4, stability improved from 1.1 to 4.5, and function improved from 2.5 to 3.8. Postoperative average ranges of motion were 180° of forward elevation, 72° of external rotation with the arm at the side, 92° of external rotation with the arm at 90° of abduction, and 90° of internal rotation with the arm at 90° of abduction. Ninety-five percent of the patients were satisfied with the procedure. Five patients suffered a recurrent dislocation, four from significant trauma. One additional patient experienced an episode of subluxation early in the recovery period. According to the criteria of Rowe, 90% had excellent or good results.     

Biceps tendon and superior labral injuries

Twenty-two patients sustained injury to the biceps tendon, rotator cuff interval, or superior labrum. Seven patients with "interval lesions" underwent biceps tenodesis, one biceps repair, and three subscapularis repairs. All were satisfied, although one tenodesis failed with distal biceps retraction. Key arthroscopic findings included biceps or subscapularis fraying. Thirteen patients with "S.L.A.P. (superior labrum anterior to posterior) lesions" underwent labral debridement. All but one obtained pain relief. Eight cadaveric shoulders exhibited extreme anatomic variability of the bicipital origin/superior labral attachment. Biomechanical study showed anterior-superior and posterior-superior labral strain with simulated biceps contraction to be greatest in shoulder abduction (p < 0.01). Biceps tendon strain was greatest in shoulder adduction (p < 0.05). A continuum of injuries to the biceps tendon exist, from the rotator cuff interval to the labral attachment. Key arthroscopic findings may assist in the difficult diagnosis of interval lesions. Individual anatomy and mechanism of injury may determine the site of the lesion.