Small molecule delivery through nanofibrous scaffolds for musculoskeletal regenerative engineering.

Musculoskeletal regenerative engineering approach using small bioactive molecules in conjunction with advanced materials has emerged as a highly promising strategy for musculoskeletal repair and regeneration. Advanced biomaterials technologies have revealed nanofiber-based scaffolds for musculoskeletal tissue engineering as vehicles for the controlled delivery of small molecule drugs. This review article highlights recent advances in nanofiber-based delivery of small molecules for musculoskeletal regenerative engineering. The article concludes with perspectives on the challenges and future directions. FROM THE CLINICAL EDITOR: In this review, advances in nanofiber-based delivery of small molecules are discussed from the standpoint of their potential role in musculoskeletal regenerative engineering, highlighting both future directions and current challenges.

Transthoracic surgical treatment for centrally located thoracic disc herniations presenting with myelopathy: a 5-year institutional experience.

STUDY DESIGN: Retrospective review. OBJECTIVE: Review clinical outcomes for myelopathic patients undergoing transthoracic discectomies for central calcified herniations. SUMMARY OF BACKGROUND DATA: Ideal surgical treatment for thoracic disc herniation is controversial due to variations in patient presentation, pathology, and possible surgical approach. Although discectomy may lead to improvements in neurologic function, it can be complicated by approach-related morbidity, especially for ventral calcified disc herniations. Review of clinical outcomes for myelopathic patients undergoing transthoracic discectomies for central calcified herniations was completed, paying special attention to neurologic status and procedure-related complications. METHODS: Between 2002 and 2007, 27 myelopathic patients were treated with 28 transthoracic surgeries for centrally located symptomatic calcified thoracic disc herniations over the last 5 years at a single institution. Demographic data, details of surgery, preoperative and postoperative Nurick and American Spinal Injury Association scores, length of stay, complications, and follow-up data were collected in all patients. RESULTS: A total of 27 patients, 8 male (30%) and 19 female (70%) with an average age of 52.3 years (range: 19 to 72) underwent 28 thoracotomies. All had myelopathy whereas 6/27 also had radicular pain syndromes. Fourteen patients had anterior instrumentation alone, 3 had anterior and posterior instrumentation, and 1 had posterior instrumentation alone. Average Nurick grade was 2.5 preoperatively and 1.4 postoperatively. Of note, American Spinal Injury Association scores improved postoperatively in 12/27 patients (10D to 10E; 2C to 2D), remained unchanged in 13/27 (11E to 11E, 2D to 2D), and worsened in 2/27 (2D to 2C). Average length of stay was 7 days (range: 3 to 15). All patients required chest tube placement with average duration of 4 days (range: 1 to 7). Major complications occurred in 6 cases (21.4%) over an average follow-up of 12 months (range: 1 to 40 mo). CONCLUSIONS: Thoracotomy for treatment of centrally located thoracic disc herniations is associated with improvement in or stabilization of myelopathic symptoms in the majority of patients with an acceptable rate of complications. Interestingly, most patients with weakness improved in strength (12/16, 75%), no patients with normal strength developed new weakness (10/10, 100%), and only 2 patients had new weakness noted postoperatively (7.4%).

Perioperative challenges in the surgical management of ankylosing spondylitis.

Patients with ankylosing spondylitis (AS) who present with spinal lesions are at an increased risk for developing perioperative complications. Due to the rigid yet brittle nature of the ankylosed spines commonly occurring with severe spinal deformity, patients are more prone to developing neurological deficits. Such risks are potentially increased not only during surgical manipulation or deformity correction, but also during image acquisition, positioning within the operating room, and intubation. In this review the complications of AS are reviewed, and recommendations are provided to avoid problems during each stage of patient management.

Supraciliary keyhole craniotomy for brain abscess debridement.

OBJECT: Treatments for brain abscesses have typically involved invasive craniotomies followed by debridement. These methods often require large incisions with vast exposure and may be associated with high morbidity rates. For supraorbital lesions of the anterior and middle cranial fossa, minimally invasive craniotomies may limit exposure and decrease surgically related morbidity while allowing adequate debridement and decompression. The authors report their experience in treating frontal epidural abscesses in pediatric patients through minimally invasive supraciliary craniotomies over a 4-year period. METHODS: Three pediatric patients with frontal epidural abscesses underwent minimally invasive debridement procedures. Each procedure consisted of a supraciliary incision and a small craniotomy to expose the abscess. All patients underwent pre- and postoperative radiological evaluation including computed tomography and magnetic resonance imaging. Data were collected on preoperative characteristics, operative management, and postoperative outcomes. RESULTS: Two patients were male and 1 patient was female. The ages of the patients ranged from 6 to 10 years (mean 8 years). A frontal abscess was diagnosed in all patients, and all were treated surgically without perioperative complications. Microbes cultured postoperatively included methicillin-resistant Staphylococcus aureus in 2 patients and Staphylococcus viridans in 1 patient. The mean follow-up duration was 12.3 months. No neurological or vascular complications were noted during follow-up. All patients were treated with antibiotics postoperatively and experienced resolution of symptoms and excellent outcomes. CONCLUSIONS: Frontal epidural abscesses can be adequately and safely debrided via a minimally invasive supraciliary craniotomy. This approach has a cosmetic benefit and may decrease approach-related morbidity.

Evaluation of factors associated with postoperative infection following sacral tumor resection.

OBJECT: Resection of sacral tumors has been shown to improve survival, since the oncological prognosis is commonly correlated with the extent of local tumor control. However, extensive soft-tissue resection in close proximity to the rectum may predispose patients to wound complications and infection. To identify potential risk factors, a review of clinical outcomes for sacral tumor resections over the past 5 years at a single institution was completed, paying special attention to procedure-related complications. METHODS: Between 2002 and 2007, 46 patients with sacral tumors were treated with surgery. Demographic data, details of surgery, type of tumor, and patient characteristics associated with surgical site infections (SSIs) were collected; these data included presence of the following variables: diabetes, obesity, smoking, steroid use, previous surgery, previous radiation, cerebrospinal fluid leak, number of spinal levels exposed, instrumentation, number of surgeons scrubbed in to the procedure, serum albumin level, and combined anterior-posterior approach. Logistic regression analysis was implemented to find an association of such variables with the presence of SSI. RESULTS: A total of 46 patients were treated for sacral tumor resections; 20 were male (43%) and 26 were female (57%), with an average age of 46 years (range 11-83 years). Histopathological findings included the following: chordoma in 19 (41%), ependymoma in 5 (11%), rectal adenocarcinoma in 5 (11%), giant cell tumor in 4 (9%), and other in 13 (28%). There were 18 cases of wound infection (39%), and 2 cases of repeat surgery for tumor recurrence (1 chordoma and 1 giant cell tumor). Factors associated with increased likelihood of infection included previous lumbosacral surgery (p = 0.0184; odds ratio [OR] 7.955) and number of surgeons scrubbed in to the operation (p = 0.0332; OR 4.018). Increasing age (p = 0.0864; OR 1.031), presence of complex soft-tissue reconstruction (p = 0.118; OR 3.789), and bowel and bladder dysfunction (p = 0.119; OR 2.667) demonstrated a trend toward increased risk of SSI. CONCLUSIONS: Patients undergoing sacral tumor surgery may be at greater risk for developing wound complications due to the extensive soft-tissue resections often required, especially with the increased potential for contamination from the neighboring rectum. In this study, it appears that previous lumbosacral surgery, number of surgeons scrubbed in, patient age, bowel and bladder dysfunction, and complex tissue reconstruction may predict those patients more prone to developing postoperative SSIs.

Nanofiber/Microsphere Hybrid Matrices In Vivo for Bone Regenerative Engineering: A Preliminary Report.

The demand for bone grafts has led to advances in regenerative engineering, a field at the intersection of advanced biomaterials, stem cell science, physics, developmental biology, and clinical translation. In this work, the authors evaluated a hybrid nanofiber/microsphere matrices both in vitro and in vivo for its ability to promote bone regeneration. Quantitative measures of cellular characteristics in vitro showed a higher fraction of marrow stromal cells with collagen promoter activity on hybrid matrices compared to control matrices (41% vs. 24%, p = 0.02). Control and hybrid matrices were then implanted for 6 weeks in calvarial defects of mice, and the animals received a single injection of calcein 1 day prior to sacrifice to visualize bone formation. Cryohistology of the undecalfied implants were evaluated for markers of bone mineralization, which revealed evidence of higher levels of bone tissue formation in hybrid matrices compared to controls. These data provide support that nanofiber-permeated, sintered, composite microsphere matrices may be a particularly useful matrix for the regenerative engineering of bone.

Neuroendoscopy: past, present, and future.

Neuroendoscopy began with a desire to visualize the ventricles and deeper structures of the brain. Unfortunately, the technology available to early neuroendoscopists was not sufficient in most cases for these purposes. The unique perspective that neuroendoscopy offered was not fully realized until key technological advances made reliable and accurate visualization of the brain and ventricles possible. After this technology was incorporated into the device, neuroendoscopic procedures were rediscovered by neurosurgeons. Endoscopic third ventriculostomy and other related procedures are now commonly used to treat a wide array of neurosurgically managed conditions. A seemingly limitless number of neurosurgical applications await the endoscope. In the future, endoscopy is expected to become routine in modern neurosurgical practice and training.

Nanofiber-microsphere (nano-micro) matrices for bone regenerative engineering: a convergence approach toward matrix design.

Bone is an essential organ for health and quality of life. Due to current shortfalls in therapy for bone tissue engineering, scientists have sought the application of synthetic materials as bone graft substitutes. As a composite organic/inorganic material with significant extra cellular matrix (ECM), one way to improve bone graft substitutes may be to engineer a synthetic matrix that is influenced by the physical appearance of natural ECM networks. In this work, the authors evaluate composite, hybrid scaffolds for bone tissue engineering based on composite ceramic/polymer microsphere scaffolds with synthetic ECM-mimetic networks in their pore spaces. Using thermally induced phase separation, nanoscale fibers were deposited in the pore spaces of structurally sound microsphere-based scaffold with a density proportionate to the initial polymer concentration. Porosimetry and mechanical testing indicated no significant changes in overall pore characteristics or mechanical integrity as a result of the fiber deposition process. These scaffolds displayed adequate mechanical integrity on the scale of human trabecular bone and supported the adhesion and proliferation of cultured mouse calvarial osteoblasts. Drawing from natural cues, these scaffolds may represent a new avenue forward for advanced bone tissue engineering scaffolds.

Small-molecule based musculoskeletal regenerative engineering.

Clinicians and scientists working in the field of regenerative engineering are actively investigating a wide range of methods to promote musculoskeletal tissue regeneration. Small-molecule-mediated tissue regeneration is emerging as a promising strategy for regenerating various musculoskeletal tissues and a large number of small-molecule compounds have been recently discovered as potential bioactive molecules for musculoskeletal tissue repair and regeneration. In this review, we summarize the recent literature encompassing the past 4 years in the area of small bioactive molecules for promoting repair and regeneration of various musculoskeletal tissues including bone, muscle, cartilage, tendon, and nerve.

Poly aspartic acid peptide-linked PLGA based nanoscale particles: potential for bone-targeting drug delivery applications.

Delivering drugs specifically to bone tissue is very challenging due to the architecture and structure of bone tissue. Poly(lactic-co-glycolic acid) (PLGA)-based nanoparticles (NPs) hold great promise for the delivery of therapeutics to bone tissue. The goal of the present research was to formulate a PLGA-based NP drug delivery system for bone tissue exclusively. Since poly-aspartic acids (poly-Asp) peptide sequence has been shown to bind to hydroxyapatite (HA), and has been suggested as a molecular tool for bone-targeting applications, we fabricated PLGA-based NPs linked with poly-Asp peptide sequence. Nanoparticles made of methoxy - poly(ethylene glycol) (PEG)-PLGA and maleimide-PEG-PLGA were prepared using a water-in-oil-in-water double emulsion and solvent evaporation method. Fluorescein isothiocyanate (FITC)-tagged poly-Asp peptide was conjugated to the surface of the nanoparticles via the alkylation reaction between the sulfhydryl groups at the N-terminal of the peptide and the CC double bond of maleimide at one end of the polymer chain to form thioether bonds. The conjugation of FITC-tagged poly-Asp peptide to PLGA NPs was confirmed by NMR analysis and fluorescent microscopy. The developed nanoparticle system is highly aqueous dispersible with an average particle size of ∼80 nm. In vitro binding analyses demonstrated that FITC-poly-Asp NPs were able to bind to HA gel as well as to mineralized matrices produced by human mesenchymal stem cells and mouse bone marrow stromal cells. Using a confocal microscopy technique, an ex vivo binding study of mouse major organ ground sections revealed that the FITC-poly-Asp NPs were able to bind specifically to the bone tissue. In addition, proliferation studies indicated that our FITC-poly-Asp NPs did not induce cytotoxicity to human osteoblast-like MG63 cell lines. Altogether, these promising results indicated that this nanoscale targeting system was able to bind to bone tissue specifically and might have a great potential for bone disease therapy in clinical applications.

Long-term clinical outcomes following en bloc resections for sacral chordomas and chondrosarcomas: a series of twenty consecutive patients.

STUDY DESIGN: Retrospective study of 20 consecutive patients who underwent en bloc tumor excision of sacral chordomas and chondrosarcomas. OBJECTIVE: To evaluate the functional and oncological outcomes following en bloc tumor excision for sacral chordomas and chondrosarcomas. SUMMARY OF BACKGROUND DATA: Chordomas and chondrosarcomas are 2 of the most common malignant primary tumors of the sacrum in adults. To date, few large clinical series with en bloc resection of these tumors exist. METHODS: An institutional primary spine tumor surgical database was retrospective reviewed. Twenty consecutive patients with sacral chordomas and chondrosarcomas who underwent primary en bloc tumor excisions from 2002 to 2007 were included in the study. Surgical margin, perioperative complications, and postoperative functional status in these patients were analyzed. Disease-free survival following en bloc tumor excision was determined using the Kaplan-Meier method. RESULTS: The study cohort included 8 males and 12 females with an average age of 53.5 years and a man follow-up of 47.8 months. Wide or marginal en bloc resection was achieved in 14 patients. In 6 other patients, tumor was identified at the surgical margins, and they were considered to have contaminated/intralesional resections. The 30-day perioperative morbidities in this series included 1 death from pulmonary embolism and 9 wound complications. Forty percent of the patients had normal bladder and bowel functions after surgery, while 60% of the patients had partial or complete loss of bladder and bowel functions. All but 2 patients in this group remained ambulatory after the surgery. The mean disease-free survival for patients with wide or marginal en bloc tumor excisions was 51 months, but the mean disease-free survival was only 17.5 months for patients who had contaminated/intralesional resections. CONCLUSION: Wide or marginal en bloc excision of sacral chordoma and chondrosarcoma is associated with significant improvement in disease-free survival with acceptable perioperative morbidity rate.

En bloc spondylectomy for treatment of tumor-induced osteomalacia.

En bloc spondylectomy represents a radical resection of a spinal segment most often reserved for patients presenting with a primary extradural spine tumor or a solitary metastasis in the setting of an indolent, well-controlled systemic malignancy. The authors report a case in which en bloc spondylectomy was conducted to control a metabolically active spine tumor. A 56-year-old woman, who suffered from severe tumor-induced osteomalacia, was found to have a fibroblast growth factor-23-secreting phosphaturic mesenchymal tumor in the T-8 vertebral body. En bloc resection was conducted, leading to resolution of her tumor-induced osteomalacia. This case suggests that radical spondylectomy may be beneficial in the management of metabolically or endocrinologically active tumors of the spine.

Adjuvant treatment with locally delivered OncoGel delays the onset of paresis after surgical resection of experimental spinal column metastasis.

OBJECTIVE: The optimal management of spinal column metastatic disease is controversial. Local chemotherapy delivery systems allow targeted high-dose adjuvant therapy. We evaluated whether injection of OncoGel paclitaxel-releasing biodegradable polymer (Protherics, Inc., West Valley City, UT) into the tumor resection cavity at the time of surgery would improve the efficacy of surgical resection with or without external beam radiotherapy (XRT) in a rat model of spinal column metastases. METHODS: Fischer-344 rats (Charles River Laboratories, Wilmington, MA) underwent a transabdominal approach for implantation of a CRL-1666 breast adenocarcinoma cell line within the L6 vertebral body. In experiment 1, 7 days after tumor implantation, animals underwent 1 of 2 treatments or no treatment (n = 8 per group): control (no treatment); surgery alone (L6 corpectomy); or surgery + OncoGel (L6 corpectomy with OncoGel implantation into the resection cavity). In experiment 2, 7 days after tumor implantation, animals underwent 1 of 2 treatments or no treatment (n = 8 per group): control (no treatment); surgery + XRT (L6 corpectomy followed by XRT [total 20 Gy]); or surgery + XRT + OncoGel (L6 corpectomy with OncoGel implantation followed by XRT). In experiment 3, 7 days after tumor implantation, animals underwent 1 of 2 treatments or no treatment (n = 8 per group): control (no treatment); XRT alone (total 20 Gy); or XRT + OncoGel. Daily hindlimb function was assessed using the Basso, Beattie, and Bresnahan (BBB) scale (range, 1-21). RESULTS: In experiment 1, both treatment groups had delayed onset of paresis compared with control. Compared with surgery alone, surgery + OncoGel resulted in superior median BBB scores on posttreatment days 9 (21 versus 19, P < 0.001) through 14 (11 versus 8, P < 0.005). In experiment 2, both treatment groups had delayed onset of paresis compared with control. Compared with surgery + XRT, surgery + XRT + OncoGel resulted in superior median BBB scores on posttreatment days 13 (21 versus 19, P < 0.001) through 17 (12 versus 8, P < 0.005). Median time to loss of ambulation (BBB scale score