Minhwan Chung

Multiple congenital brachymetatarsia: A ONE-STAGE COMBINED SHORTENING AND LENGTHENING PROCEDURE WITHOUT ILIAC BONE GRAFT

We performed nine metatarsal and three proximal phalangeal lengthenings in five patients with congenital brachymetatarsia of the first and one or two other metatarsal bones, by a one-stage combined shortening and lengthening procedure using intercalcary autogenous bone grafts from adjacent shortened metatarsal bones. Instead of the isolated lengthening of the first and the other metatarsal bones, we shortened the adjacent normal metatarsal and used the excised bone to lengthen the short toes, except for the great toe, to restore the normal parabola. One skin incision was used. All the operations were performed bilaterally and the patients were followed up for a mean period of 69.5 months (29 to 107). They all regained a nearly normal parabola and were satisfied with the cosmetic results. Our technique is straightforward and produces good cosmetic results. Satisfactory, bony union is achieved, morbidity is low, and no additional surgery is required for the removal of metal implants.

Frequency modulation of ERK activation dynamics rewires cell fate

Transient versus sustained ERK MAP kinase (MAPK) activation dynamics induce proliferation versus differentiation in response to epidermal (EGF) or nerve (NGF) growth factors in PC‐12 cells. Duration of ERK activation has therefore been proposed to specify cell fate decisions. Using a biosensor to measure ERK activation dynamics in single living cells reveals that sustained EGF/NGF application leads to a heterogeneous mix of transient and sustained ERK activation dynamics in distinct cells of the population, different than the population average. EGF biases toward transient, while NGF biases toward sustained ERK activation responses. In contrast, pulsed growth factor application can repeatedly and homogeneously trigger ERK activity transients across the cell population. These datasets enable mathematical modeling to reveal salient features inherent to the MAPK network. Ultimately, this predicts pulsed growth factor stimulation regimes that can bypass the typical feedback activation to rewire the system toward cell differentiation irrespective of growth factor identity.

A bioengineered array of 3D microvessels for vascular permeability assay.

Blood vessels exhibit highly regulated barrier function allowing selective passage of macromolecules. Abnormal vascular permeability caused by disorder in barrier function is often associated with various pathological states such as tumor progression or pulmonary fibrosis. There are no realistic in vitro models for measuring vascular permeability as most models are limited to mimicking anatomical structural properties of in vivo vessel barriers. This paper presents a reliable microfluidic-based chip for measuring permeability by engineering tubular perfusable microvessels. This platform is compatible with high resolution, live-cell time-lapse imaging and high throughput permeability measurements. The microvessels were formed by natural angiogenic process and thus exhibit reliable barrier properties with permeability coefficient of 1.55×10(-6)cm/s (for 70kDa FITC-dextran). The bioengineered microvessels showed properties similar to in vivo vessels in terms of cell-cell junction expression (ZO-1, Claudin-5 and VE-cadherin) and response to agonists such as histamine and TNF-α. We showed that hyperpermeability of the tumor microvessel could be normalized with anti-VEGF (bevacizumab) treatment, consistent with the mechanism of action for bevacizumab. The method developed here provides a relatively simple, robust technique for assessing drug effects on permeability of microvessels with a number of potential applications in fundamental vascular biology as well as drug screening.

Engineering of a Biomimetic Pericyte-Covered 3D Microvascular Network

Pericytes enveloping the endothelium play an important role in the physiology and pathology of microvessels, especially in vessel maturation and stabilization. However, our understanding of fundamental pericyte biology is limited by the lack of a robust in vitro model system that allows researchers to evaluate the interactions among multiple cell types in perfusable blood vessels. The present work describes a microfluidic platform that can be used to investigate interactions between pericytes and endothelial cells (ECs) during the sprouting, growth, and maturation steps of neovessel formation. A mixture of ECs and pericytes was attached to the side of a pre-patterned three dimensional fibrin matrix and allowed to sprout across the matrix. The effects of intact coverage and EC maturation by the pericytes on the perfused EC network were confirmed using a confocal microscope. Compared with EC monoculture conditions, EC-pericyte co-cultured vessels showed a significant reduction in diameter, increased numbers of junctions and branches and decreased permeability. In response to biochemical factors, ECs and pericytes in the platform showed the similar features with previous reports from in vivo experiments, thus reflect various pathophysiological conditions of in vivo microvessels. Taken together, these results support the physiological relevancy of our three-dimensional microfluidic culture system but also that the system can be used to screen drug effect on EC-pericyte biology.

Two extension block Kirschner wire technique for mallet finger fractures

We treated 32 displaced mallet finger fractures by a two extension block Kirschner-wire technique. The clinical and radiological outcomes were evaluated at a mean follow-up of 49 months (25 to 84). The mean joint surface involvement was 38.4% (33% to 50%) and 18 patients (56%) had accompanying joint subluxation. All 32 fractures united with a mean time to union of 6.2 weeks (5.1 to 8.2). Congruent joint surfaces and anatomical reduction were seen in all cases. The mean flexion of the distal interphalangeal joints was 83.1 degrees (75 degrees to 90 degrees ) and the mean extension loss was 0.9 degrees (0 degrees to 7 degrees ). No digit had a prominent dorsal bump or a recurrent mallet deformity. We believe that this technique, when properly applied, produces satisfactory results both clinically and radiologically.

Changes in ulnar variance in relation to forearm rotation and grip

We studied radiographs of the wrists of 120 healthy volunteers in order to determine the normal range of ulnar variance. They had been taken in various positions under both unloaded (static) and loaded (dynamic) conditions. Pronation posteroanterior, supination anteroposterior and neutral posteroanterior views were taken of each wrist before and during a maximum grip under identical conditions. The mean normal ulnar variance in neutral rotation was +0.74+/-1.46 mm, a value which was significantly lower in males than in females. We found negative variance in 26% of cases. We measured maximum ulnar variance (UVmax +1.52+/-1.56 mm) when gripping in pronation and minimum ulnar variance (UVmin +0.19+/-1.43 mm) when relaxed in supination. We subtracted UVmin from UVmax to calculate a mean maximum dynamic change in ulnar variance of 1.34+/-0.53 mm. We consider this database of normal values to be useful for both the diagnosis and treatment of conditions related to discrepancy in radio-ulnar length and for clinical research.

Interstitial flow regulates the angiogenic response and phenotype of endothelial cells in a 3D culture model

A crucial yet ill-defined phenomenon involved in the remodeling of vascular networks, including angiogenic sprouting, is flow-mediated endothelial dynamics and phenotype changes. Despite interstitial flow (IF) being ubiquitously present in living tissues surrounding blood capillaries, it is rarely investigated and poorly understood how endothelial cells respond to this flow during morphogenesis. Here we develop a microfluidic 3D in vitro model to investigate the role of IF during vasculogenic formation and angiogenic remodeling of microvascular networks. In the presented model, human blood endothelial cells co-cultured with stromal fibroblasts spontaneously organize into an interconnected microvascular network and then further expand to adjacent avascular regions in a manner of neovessel sprouting. We found that in the presence of IF, vasculogenic organization of the microvascular network was significantly facilitated regardless of the flow direction, whereas angiogenic sprouting was promoted only when the directions of flow and sprouting were opposite while angiogenic activity was suppressed into the direction of flow. We also observed that the vasculatures switch between active angiogenic remodeling and quiescent/non-sprouting state in the contexts provided by IF. This regulatory effect can be utilized to examine the role of anti-angiogenic compounds, clearly distinguishing the differential influences of the compounds depending on their mechanisms of action. Collectively, these results suggest that IF may serve as a critical regulator in tissue vascularization and pathological angiogenesis.

Musculofascial lengthening for the treatment of patients with medial epicondylitis and coexistent ulnar neuropathy

The outcome of surgery in patients with medial epicondylitis of the elbow is less favourable in those with co-existent symptoms from the ulnar nerve. We wanted to know whether we could successfully treat such patients by using musculofascial lengthening of the flexor-pronator origin with simultaneous deep transposition of the ulnar nerve. We retrospectively reviewed 19 patients who were treated in this way. Seven had grade I and 12 had grade IIa ulnar neuropathy. At a mean follow-up of 38 months (24 to 48), the mean visual analogue scale pain scores improved from 3.7 to 0.3 at rest, from 6.6 to 2.1 with activities of daily living, and from 7.9 to 2.3 at work or sports, and the mean disabilities of the arm, shoulder and hand scores improved from 42.2 to 23.5. These results suggest that this technique can be effective in treating patients with medial epicondylitis and coexistent ulnar nerve symptoms.

Complications of distraction lengthening in the hand

This study examined the features of 16 complications from 51 distraction lengthenings in the hands of 43 patients. From 1996 to 2006, 24 metacarpals and 27 phalanges were lengthened at a rate of 0.5 and 0.25 mm/day, respectively, using a callus distraction technique. The indications were congenital (33 cases in 27 patients) and traumatic (18 cases in 16 patients) deformities. The average percentage lengthening in the phalanges and metacarpals was 62% (16 mm) and 63% (34 mm), respectively. The distraction rates in the phalanges and metacarpals were 69 and 52 days/cm, respectively. The overall complication rate was 31%. Major complications requiring secondary procedures were non-union (one case), fracture (one case), premature union (one case), angulations (two cases) and dislodgment of pins (two cases). The minor complications encountered were delayed callus formation (four cases), joint stiffness (four cases) and soft tissue thinning (one case). Traumatic deformities had more complications than the congenital ones (nine of 18 cases and seven of 33 cases, respectively). The phalanges had a higher rate of complication than the metacarpals (11 of 27 cases and four of 24 cases, respectively). Most patients with complications except for two children with dislodgment were as satisfied with the final results as those without complications. Although callus distraction in the hand requires a long treatment period and has a relatively high rate of complication, it appears to be effective in achieving adequate bone length. A high level of patient compliance and prompt management of complications by an experienced surgeon are essential for achieving good results.

Wet-AMD on a Chip: Modeling Outer Blood-Retinal Barrier In Vitro

Choroidal neovascularization (CNV) in the retinal pigment epithelium (RPE)-choroid complex constituting outer blood retinal barrier (oBRB) is a critical pathological step in various ophthalmic diseases, which results in blindness, such as wet type age-related macula degeneration. Current in vitro experimental models using petri dishes or transwell are unable to study CNV morphogenesis. Here, a unique organotypic eye-on-a-chip model is described that mimics the RPE-choroid complex in vitro. This model consists of an RPE monolayer and adjacent perfusable blood vessel network, which is supporting barrier function of oBRB. The intact barrier function of the RPE-choroid complex is reconstituted while maintaining important structural features. Further, this model can successfully mimic the pathogenesis of CNV especially in terms of morphogenesis, which is penetrating angiogenic sprouts from pre-existing choroidal vessels that result in breakdown of RPE monolayer. The alleviation of the pathological angiogenesis can be modeled with bevacizumab, a clinical drug for CNV treatment. It is believed that this model can be used to aid in the development of advanced in vitro eye drug evaluation in conjunction with animal models.