Melanie R. Major

Pullulan Hydrogels Improve Mesenchymal Stem Cell Delivery into High‐Oxidative‐Stress Wounds

Cell-based therapies for wound repair are limited by inefficient delivery systems that fail to protect cells from the acute inflammatory environment. Here, a biomimetic hydrogel system is described that is based on the polymer pullulan, a carbohydrate glucan known to exhibit potent antioxidant capabilities. It is shown that pullulan hydrogels are an effective cell delivery system and improve mesenchymal stem cell survival and engraftment in high-oxidative-stress environments. The results suggest that glucan hydrogel systems may prove beneficial for progenitor-cell-based approaches to skin regeneration.

The foreign body response: at the interface of surgery and bioengineering.

Background: The surgical implantation of materials and devices has dramatically increased over the past decade. This trend is expected to continue with the broadening application of biomaterials and rapid expansion of aging populations. One major factor that limits the potential of implantable materials and devices is the foreign body response, an immunologic reaction characterized by chronic inflammation, foreign body giant cell formation, and fibrotic capsule formation. Methods: The English literature on the foreign body response to implanted materials and devices is reviewed. Results: Fibrotic encapsulation can cause device malfunction and dramatically limit the function of an implanted medical device or material. Basic science studies suggest a role for immune and inflammatory pathways at the implant-host interface that drive the foreign body response. Current strategies that aim to modulate the host response and improve construct biocompatibility appear promising. Conclusions: This review article summarizes recent basic science, preclinical, and clinicopathologic studies examining the mechanisms driving the foreign body response, with particular focus on breast implants and synthetic meshes. Understanding these molecular and cellular mechanisms will be critical for achieving the full potential of implanted biomaterials to restore human tissues and organs.

The Role of Focal Adhesion Kinase in Keratinocyte Fibrogenic Gene Expression

Abnormal skin scarring causes functional impairment, psychological stress, and high socioeconomic cost. Evidence shows that altered mechanotransduction pathways have been linked to both inflammation and fibrosis, and that focal adhesion kinase (FAK) is a key mediator of these processes. We investigated the importance of keratinocyte FAK at the single cell level in key fibrogenic pathways critical for scar formation. Keratinocytes were isolated from wildtype and keratinocyte-specific FAK-deleted mice, cultured, and sorted into single cells. Keratinocytes were evaluated using a microfluidic-based platform for high-resolution transcriptional analysis. Partitive clustering, gene enrichment analysis, and network modeling were applied to characterize the significance of FAK on regulating keratinocyte subpopulations and fibrogenic pathways important for scar formation. Considerable transcriptional heterogeneity was observed within the keratinocyte populations. FAK-deleted keratinocytes demonstrated increased expression of genes integral to mechanotransduction and extracellular matrix production, including Igtbl, Mmpla, and Col4a1. Transcriptional activities upon FAK deletion were not identical across all single keratinocytes, resulting in higher frequency of a minor subpopulation characterized by a matrix-remodeling profile compared to wildtype keratinocyte population. The importance of keratinocyte FAK signaling gene expression was revealed. A minor subpopulation of keratinocytes characterized by a matrix-modulating profile may be a keratinocyte subset important for mechanotransduction and scar formation.

Nonoperative Management of Acute Upper Limb Ischemia

Background: Acute upper limb ischemia (AULI) is an uncommon emergency warranting immediate evaluation and treatment. The role of nonsurgical therapies including endovascular techniques, thrombolytics, and anticoagulation remains undefined. The authors systematically reviewed the current literature on the nonsurgical treatment of acute ischemia of the upper extremity. Methods: A PubMed and Embase search was conducted, and articles were screened using predetermined criteria. Data collected included patient demographics, cause of upper limb ischemia, type of nonsurgical treatment used, treatment outcomes, and complications. Patients were divided into 4 treatment groups: catheter embolectomy, catheter-directed thrombolysis, endovascular stenting, and anticoagulation/medical therapy alone. Results: Twenty-three retrospective studies met the search criteria. Of 1326 reported occlusions, 92% (1221) were attributed to thromboembolic disease. The second most common cause was iatrogenic (1.5%). Overall limb salvage rates were excellent with catheter embolectomy (862 of 882 cases, 97.7%) and catheter-directed thrombolysis (110 of 114 cases, 96.5%). Limb salvage rates were also high with anticoagulation/medical therapy (158 of 165 cases, 95.8%), but poor functional outcomes were more often reported. Conclusions: High-quality evidence to guide the nonsurgical treatment of AULI is lacking. Retrospective studies support the utility of catheter-based embolectomy and thrombolysis for distal ischemia. Whether a surgical or nonsurgical approach is taken, anticoagulation therapy remains a mainstay of both treatment and prevention of AULI. Because AULI patients often have underlying cardiac and/or systemic disease, a multidisciplinary approach is essential to minimize complications and prevent future occurrences.

The Effect of Timing on Breast Reconstruction Outcomes in Diabetic Women

Background: This study examines the effect of timing (immediate vs delayed) on postoperative morbidity in diabetic women undergoing breast reconstruction after mastectomy. Methods: We reviewed the National Surgical Quality Improvement Program (NSQIP) databases from 2005 to 2012 for all diabetic women undergoing breast reconstruction. Multivariable logistic regression was used to estimate the risk of 30-day overall complications in the immediate versus delayed cohorts. Additionally, we retrospectively reviewed outcomes for all Johns Hopkins Hospital diabetic patients undergoing breast reconstruction from 2005 to 2014. Results: In the NSQIP, 1,408 diabetic women underwent breast reconstruction: 958 (68%) immediate and 450 (32%) delayed. In the immediate group, 10.75% of patients developed a 30-day overall complication, compared with 7.78% of patients in the delayed group. On multivariable analysis, the odds of developing 30-day overall complications were significantly higher (adjusted odds ratio = 1.68; P = 0.033) for the immediate compared with the delayed cohort. In the Johns Hopkins Hospital cohort, 114 reconstructions were performed in 52 diabetic women: 59 (51.8%) immediate and 55 (47.2%) delayed. On long-term follow-up (median = 16.5 months), 41.0% of immediate reconstructions developed a surgical complication compared with 27.8% of delayed reconstructions. Deep infections (P = 0.026), seroma formation (P = 0.003), reconstruction failure (P = 0.001), and reoperation rates (P = 0.001) were significantly increased in the immediate cohort. Conclusions: Among diabetics seeking breast reconstruction, delaying the reconstructive surgery from the mastectomy is associated with decreased postoperative morbidity. It also appears that the 30-day postoperative time point available in the NSQIP does not fully reflect the magnitude of the long-term complications these diabetic patients will develop.