Zayna Nahas

A versatile pH sensitive chondroitin sulfate–PEG tissue adhesive and hydrogel

We developed a chondroitin sulfate-polyethylene glycol (CS-PEG) adhesive hydrogel with numerous potential biomedical applications. The carboxyl groups on chondroitin sulfate (CS) chains were functionalized with N-hydroxysuccinimide (NHS) to yield chondroitin sulfate succinimidyl succinate (CS-NHS). Following purification, the CS-NHS molecule can react with primary amines to form amide bonds. Hence, using six arm polyethylene glycol amine PEG-(NH2)6 as a crosslinker we formed a hydrogel which was covalently bound to proteins in tissue via amide bonds. By varying the initial pH of the precursor solutions, the hydrogel stiffness, swelling properties, and kinetics of gelation could be controlled. The sealing/adhesive strength could also be modified by varying the damping and storage modulus properties of the material. The adhesive strength of the material with cartilage tissue was shown to be ten times higher than that of fibrin glue. Cells encapsulated or in direct contact with the material remained viable and metabolically active. Furthermore, CS-PEG material produced minimal inflammatory response when implanted subcutaneously in a rat model and enzymatic degradation was demonstrated in vitro. This work establishes an adhesive hydrogel derived from biological and synthetic components with potential application in wound healing and regenerative medicine.

The role of positron emission tomography/computed tomography in the management of recurrent papillary thyroid carcinoma

Objectives/Hypothesis: The aim of the study was to evaluate the role of combined positron emission tomography/computed tomography (PET/CT) fusion imaging in the detection and management of recurrent papillary thyroid cancer.

Photoactivated Composite Biomaterial for Soft Tissue Restoration in Rodents and in Humans

Photoactivated composite poly(ethylene glycol)–hyaluronic acid biomaterials demonstrate enhanced physicochemical properties for facial soft tissue reconstruction. Photogenic Polymers Can Fix the Flaws Some people just love the spotlight; apparently, some polymers do too. Here, Hillel et al. introduce a class of composite polymers that react favorably to light by crosslinking within minutes. These polymers, composed of synthetic poly(ethylene glycol) (PEG) and natural hyaluronic acid (HA), have been developed for reconstructing facial soft tissue. Deformities in craniofacial soft tissue are a clinical challenge because even small defects can have a major impact on a person’s social behavior and psychological well-being. Hillel and colleagues created a polymeric composite that can be injected into the damaged site, massaged into shape, and then crosslinked in situ with light. A transdermal light exposure method would allow clinicians to inject a liquid polymer, rather than surgically inserting already-polymerized material. First, the authors designed an array of light-emitting diodes to penetrate up to 4 mm of human skin (both light and dark) without any painful side effects. A 2-min exposure to light was enough to crosslink the PEG-HA material under the skin. Next, the polymer was tailored to closely match the elastic properties of native soft tissues, such as human fat. Various amounts of PEG and concentrations of HA were tested, with the authors arriving at an optimal combination of 100 mg PEG and 24 mg/ml HA. When polymerized subcutaneously in rats, the PEG-HA implants were able to maintain near their original volume for up to 491 days, whereas control HA injections were completely resorbed. Notably, these HA-based materials were partially reversible with the addition of the enzyme hyaluronidase. To translate this material to the clinic, Hillel et al. then tested the PEG-HA composites in humans. The polymer was injected into the intradermal space in the abdomen of three patients scheduled to undergo abdominoplasty surgery. Similar to the rodent studies, the PEG-HA material persisted for 12 weeks, whereas the control HA injections lost their shape. An inflammatory response was observed surrounding the injections. It is clear that this new photo-friendly polymer and transdermal crosslinking method will be clinically useful for soft tissue reconstruction—perhaps even encouraging more people to put their best faces forward in the spotlight. Soft tissue reconstruction often requires multiple surgical procedures that can result in scars and disfiguration. Facial soft tissue reconstruction represents a clinical challenge because even subtle deformities can severely affect an individual’s social and psychological function. We therefore developed a biosynthetic soft tissue replacement composed of poly(ethylene glycol) (PEG) and hyaluronic acid (HA) that can be injected and photocrosslinked in situ with transdermal light exposure. Modulating the ratio of synthetic to biological polymer allowed us to tune implant elasticity and volume persistence. In a small-animal model, implanted photocrosslinked PEG-HA showed a dose-dependent relationship between increasing PEG concentration and enhanced implant volume persistence. In direct comparison with commercial HA injections, the PEG-HA implants maintained significantly greater average volumes and heights. Reversibility of the implant volume was achieved with hyaluronidase injection. Pilot clinical testing in human patients confirmed the feasibility of the transdermal photocrosslinking approach for implantation in abdomen soft tissue, although an inflammatory response was observed surrounding some of the materials.

An injectable adipose matrix for soft-tissue reconstruction

Background: Soft-tissue repair is currently limited by the availability of autologous tissue sources and the absence of an ideal soft-tissue replacement comparable to native adipose tissue. Extracellular matrix–based biomaterials have demonstrated great potential as instructive scaffolds for regenerative medicine, mechanically and biochemically defined by the tissue of origin. As such, the distinctive high lipid content of adipose tissue requires unique processing conditions to generate a biocompatible scaffold for soft-tissue repair. Methods: Human adipose tissue was decellularized to obtain a matrix devoid of lipids and cells while preserving extracellular matrix architecture and bioactivity. To control degradation and volume persistence, the scaffold was cross-linked using hexamethylene diisocyanate and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide. In vitro studies with human adipose-derived stem cells were used to assess cell viability and adipogenic differentiation on the biomaterial. In vivo biocompatibility and volume persistence were evaluated by subcutaneous implantation over 12 weeks in a small-animal model. Results: The scaffold provided a biocompatible matrix supporting the growth and differentiation of adipose-derived stem cells in vitro. Cross-linking the matrix increased its resistance to enzymatic degradation. Subcutaneous implantation of the acellular adipose matrix in Sprague-Dawley rats showed minimal inflammatory reaction. Adipose tissue development and vascularization were observed in the implant, with host cells migrating into the matrix indicating the instructive potential of the matrix for guiding tissue remodeling and regeneration. Conclusions: With its unique biological and mechanical properties, decellularized adipose extracellular matrix is a promising biomaterial scaffold that can potentially be used allogenically for the correction of soft-tissue defects.

Spontaneous Meningoencephalocele of the Temporal Bone: Clinical Spectrum and Presentation

OBJECTIVE To describe the clinical presentation and the radiological and surgical findings in patients with spontaneous meningoencephalocele of the temporal bone. DESIGN Retrospective case series. SETTING Academic, tertiary care medical center. PATIENTS Fifteen consecutive patients with surgically confirmed meningoencephalocele of the mastoid and middle ear, without a history of trauma, tumor, cholesteatoma, or surgery of the mastoid or cranium, who were treated at our institution between January 1, 1999, and December 31, 2006. RESULTS Ten of the 15 patients were women. Ages ranged from 31 to 77 years, with 12 patients 50 years or older. The most common presenting complaint was new-onset hearing loss in 14 patients, followed by aural fullness and headache. Cerebrospinal fluid formed an effusion in the middle ears of 13 patients and was most commonly identified when myringotomy resulted in continuous clear otorrhea. Four subjects had a history of adult-onset recurrent acute otitis media with intermittent otorrhea, which in 1 case was complicated by brain abscess. At least 1 full-thickness defect of the tegmen associated with cortical thinning of the middle fossa floor was identified in all cases on high-resolution computed tomography. At surgery, herniations of meningeal and cerebral tissue were seen through 1 (7 cases) or 2 (8 cases) defects in the middle fossa floor. Obstruction of antral aeration by the meningoencephalocele was present in all 4 cases associated with otitis media. CONCLUSIONS The onset of otitis media, including middle ear effusions at 40 years or older, warrants the consideration of a meningoencephalocele of the ear. The appearance of tegmental defects and cortical thinning of the middle fossa floor on computed tomography provides a strong indication of the diagnosis and of the need for surgical repair.

Tissue Engineering for In Vitro Analysis of Matrix Metalloproteinases in the Pathogenesis of Keloid Lesions

IMPORTANCE Keloid lesions form because of alterations in the mechanisms that govern cutaneous wound healing. Although matrix metalloproteinases (MMPs) have been implicated in keloid pathophysiology, many questions still remain about their involvement. Our incomplete understanding of keloid pathophysiology has led to high recurrence rates in current treatments. No reliable animal model is available for studying keloids. OBJECTIVE To gain a better understanding of the disease mechanisms involved in keloid lesions in the hopes of identifying therapeutic options. DESIGN Fibroblasts derived from keloid tissue were incorporated in either Matrigel or polyethylene glycol diacrylate mixed with type I collagen to create 3-dimensional models to investigate the role MMPs play in keloid formation. The MMP gene expressions were also compared between fibroblasts isolated from different sites within the same keloid lesion. SETTING The Johns Hopkins School of Medicine, Baltimore, Maryland. PARTICIPANTS Keloid fibroblasts were received from the Baylor College of Medicine, and additional keloid fibroblasts were enzymatically isolated from the dermal layer of lesions removed from consenting patients at The Johns Hopkins Hospital. RESULTS In the Matrigel system, MMP9 and MMP13 were observed to be significantly upregulated in keloid fibroblasts. The addition of decorin resulted in a significant decrease of type I collagen and MMP1, MMP9, and MMP13 gene expressions from keloid fibroblasts. Higher MMP gene expressions were observed in fibroblasts isolated from the margins of the original keloid wound. CONCLUSIONS AND RELEVANCE MMP9 and MMP13 are expressed significantly more in keloid-derived cells, thus making them 2 potential targets for disease modification. Molecules that target organization of the lesions matrix can be beneficial in downregulating increased markers during the disease. In addition, heterogeneity is observed with the varying MMP gene expressions from site-specific fibroblasts within the same keloid lesion.

Validation of a small animal model for soft tissue filler characterization.

Background Rigorous preclinical testing of soft tissue fillers has been lacking. No animal model has emerged as an accepted standard to evaluate tissue filler longevity. Objective To validate a small animal model to compare soft tissue filler degradation and tissue reaction. Methods Preliminary experiments compared caliper with magnetic resonance imaging volumetric analysis. Next, four hyaluronic acid (HA) fillers were injected into the dermis of Sprague–Dawley rats. The three dimensions of the implants were measured at day 0, day 1, and monthly for 1 year or complete resorption of the filler. Volumetric, histologic, and statistical analyses were performed. Results Magnetic resonance imaging results validated caliper‐based volumetric measurements. Histology demonstrated injections in the subcutaneous space just deep to the dermis and panniculus carnosus. High‐ and very high‐concentration HA fillers maintained significantly greater volumes and volume ratios than low‐concentration HA fillers throughout the duration of the study. Conclusions The rat subcutis model demonstrated the ability to differentiate between HA fillers with different residence times. The caliper‐based rat‐subcutis method demonstrated consistent volumetric analysis and correlated with human residence times of HA fillers. These quantitative results validate the rat subcutis model as an expedited preclinical model for HA fillers.

Acellular Adipose Tissue Scaffold for Soft Tissue Reconstruction

IntroductIon: Soft tissue injury can arise from trauma, tumor resection or congenital defects. Current treatment options using autologous flaps or prosthetic implants have drawbacks that include donor site morbidity and capsular contracture, giving rise to the clinical need for a soft tissue replacement that can be used allogeneically and encourage host tissue regeneration (1-4). Adipose tissue can potentially provide a biologically instructive scaffold for soft tissue reconstruction. Using mechanical and chemical treatments to decellularize adipose tissue, the extracellular matrix (ECM) can be retained for use as a biocompatible soft tissue filler.