Zuhaib Ibrahim

Injectable bioadhesive hydrogels with innate antibacterial properties

Surgical site infections cause significant postoperative morbidity and increased healthcare costs. Bioadhesives used to fill surgical voids and support wound healing are typically devoid of antibacterial activity. Here, we report novel syringe-injectable bioadhesive hydrogels with inherent antibacterial properties prepared from mixing polydextran aldehyde (PDA) and branched polyethylenimine (PEI). These adhesives kill both Gram-negative and Gram–positive bacteria, while sparing human erythrocytes. An optimal composition of 2.5 wt % oxidized dextran and 6.9 wt % PEI sets within seconds forming a mechanically rigid (~1700 Pa) gel offering a maximum adhesive stress of ~ 2.8 kPa. A murine infection model showed that the adhesive is capable of killing S. pyogenes introduced subcutaneously at the bioadhesive’s surface, with minimal inflammatory response. The adhesive was also effective in a cecal ligation and puncture model, preventing sepsis and significantly improving survival. These bioadhesives represent novel, inherently antibacterial materials for wound filling applications.

A Critical Analysis of Rejection in Vascularized Composite Allotransplantation: Clinical, Cellular and Molecular Aspects, Current Challenges, and Novel Concepts

Advances in microsurgical techniques and immunomodulatory protocols have contributed to the expansion of vascularized composite allotransplantation (VCA) with very encouraging immunological, functional, and cosmetic results. Rejection remains however a major hurdle that portends serious threats to recipients. Rejection features in VCA have been described in a number of studies, and an international consensus on the classification of rejection was established. Unfortunately, current available diagnostic methods carry many shortcomings that, in certain cases, pose a great diagnostic challenge to physicians especially in borderline rejection cases. In this review, we revisit the features of acute skin rejection in hand and face transplantation at the clinical, cellular, and molecular levels. The multiple challenges in diagnosing rejection and in defining chronic and antibody-mediated rejection in VCA are then presented, and we finish by analyzing current research directions and novel concepts aiming at improving available diagnostic measures.

Mesenchymal Stem Cells Enhance Nerve Regeneration in a Rat Sciatic Nerve Repair and Hindlimb Transplant Model

This study investigates the efficacy of local and intravenous mesenchymal stem cell (MSC) administration to augment neuroregeneration in both a sciatic nerve cut-and-repair and rat hindlimb transplant model. Bone marrow-derived MSCs were harvested and purified from Brown-Norway (BN) rats. Sciatic nerve transections and repairs were performed in three groups of Lewis (LEW) rats: negative controls (n = 4), local MSCs (epineural) injection (n = 4), and systemic MSCs (intravenous) injection (n = 4). Syngeneic (LEW-LEW) (n = 4) and allogeneic (BN-LEW) (n = 4) hindlimb transplants were performed and assessed for neuroregeneration after local or systemic MSC treatment. Rats undergoing sciatic nerve cut-and-repair and treated with either local or systemic injection of MSCs had significant improvement in the speed of recovery of compound muscle action potential amplitudes and axon counts when compared with negative controls. Similarly, rats undergoing allogeneic hindlimb transplants treated with local injection of MSCs exhibited significantly increased axon counts. Similarly, systemic MSC treatment resulted in improved nerve regeneration following allogeneic hindlimb transplants. Systemic administration had a more pronounced effect on electromotor recovery while local injection was more effective at increasing fiber counts, suggesting different targets of action. Local and systemic MSC injections significantly improve the pace and degree of nerve regeneration after nerve injury and hindlimb transplantation.

Microvascular anastomosis guidance and evaluation using real-time three-dimensional Fourier-domain Doppler optical coherence tomography

Abstract. Vascular and microvascular anastomoses are critical components of reconstructive microsurgery, vascular surgery, and transplant surgery. Intraoperative surgical guidance using a surgical imaging modality that provides an in-depth view and three-dimensional (3-D) imaging can potentially improve outcome following both conventional and innovative anastomosis techniques. Objective postoperative imaging of the anastomosed vessel can potentially improve the salvage rate when combined with other clinical assessment tools, such as capillary refill, temperature, blanching, and skin turgor. Compared to other contemporary postoperative monitoring modalities—computed tomography angiograms, magnetic resonance (MR) angiograms, and ultrasound Doppler—optical coherence tomography (OCT) is a noninvasive high-resolution (micron-level), high-speed, 3-D imaging modality that has been adopted widely in biomedical and clinical applications. For the first time, to the best of our knowledge, the feasibility of real-time 3-D phase-resolved Doppler OCT (PRDOCT) as an assisted intra- and postoperative imaging modality for microvascular anastomosis of rodent femoral vessels is demonstrated, which will provide new insights and a potential breakthrough to microvascular and supermicrovascular surgery.

Diagnosing skin rejection in vascularized composite allotransplantation: advances and challenges

Refinements in microsurgical techniques coupled with advances in immunosuppressive and immunomodulatory protocols have enabled broader clinical application of vascularized composite allotransplantation (VCA) with encouraging immunological, functional, and esthetic results. However, skin rejection remains a significant obstacle and a serious complication for VCA recipients. Clinical and histopathological features of rejection in VCA have been described in a number of studies, which led to the development of an international consensus on the classification guidelines of rejection in the context of VCA. Nevertheless, currently available diagnostic modalities still have several limitations and shortcomings that can pose a significant diagnostic challenge, particularly when signs of rejection are found to be equivocal. In this review, we provide a critical analysis of these advances and challenges in diagnosing skin rejection. Specifically, we highlight the gaps in understanding of rejection mechanisms, the shortfalls in correlating cellular, molecular, and clinicopathologic markers with rejection grades, deficiencies in defining chronic rejection, and antibody‐mediated rejection after VCA, as well as providing an outlook on novel concepts, such as the utilization of advanced computational analyses and cross‐disciplinary diagnostic approaches.

Stem Cell-Based Approaches to Improve Nerve Regeneration: Potential Implications for Reconstructive Transplantation?

Reconstructive transplantation has become a viable option to restore form and function after devastating tissue loss. Functional recovery is a key determinant of overall success and critically depends on the quality and pace of nerve regeneration. Several molecular and cell-based therapies have been postulated and tested in pre-clinical animal models to enhance nerve regeneration. Schwann cells remain the mainstay of research focus providing neurotrophic support and signaling cues for regenerating axons. Alternative cell sources such as mesenchymal stem cells and adipose-derived stromal cells have also been tested in pre-clinical animal models and in clinical trials due to their relative ease of harvest, rapid expansion in vitro, minimal immunogenicity, and capacity to integrate and survive within host tissues, thereby overcoming many of the challenges faced by culturing of human Schwann cells and nerve allografting. Induced pluripotent stem cell-derived Schwann cells are of particular interest since they can provide abundant, patient-specific autologous Schwann cells. The majority of experimental evidence on cell-based therapies, however, has been generated using stem cell-seeded nerve guides that were developed to enhance nerve regeneration across “gaps” in neural repair. Although primary end-to-end repair is the preferred method of neurorrhaphy in reconstructive transplantation, mechanistic studies elucidating the principles of cell-based therapies from nerve guidance conduits will form the foundation of further research employing stem cells in end-to-end repair of donor and recipient nerves. This review presents key components of nerve regeneration in reconstructive transplantation and highlights the pre-clinical studies that utilize stem cells to enhance nerve regeneration.

Near-infrared lymphography as a minimally invasive modality for imaging lymphatic reconstitution in a rat orthotopic hind limb transplantation model

Wider application of vascularized composite allotransplantation (VCA) is limited by the need for chronic immunosuppression. Recent data suggest that the lymphatic system plays an important role in mediating rejection. This study used near‐infrared (NIR) lymphography to describe lymphatic reconstitution in a rat VCA model. Syngeneic (Lewis–Lewis) and allogeneic (Brown Norway–Lewis) rat orthotopic hind limb transplants were performed without immunosuppression. Animals were imaged pre‐ and postoperatively using indocyanine green (ICG) lymphography. Images were collected using an NIR imaging system. Co‐localization was achieved through use of an acrylic paint/hydrogen peroxide mixture. In all transplants, ICG first crossed graft suture lines on postoperative day (POD) 5. Clinical signs of rejection also appeared on POD 5 in allogeneic transplants, with most exhibiting Grade 3 rejection by POD 6. Injection of an acrylic paint/hydrogen peroxide mixture on POD 5 confirmed the existence of continuous lymphatic vessels crossing the suture line and draining into the inguinal lymph node. NIR lymphography is a minimally invasive imaging modality that can be used to study lymphatic vessels in a rat VCA model. In allogeneic transplants, lymphatic reconstitution correlated with clinical rejection. Lymphatic reconstitution may represent an early target for immunomodulation.

Minimization of Immunosuppression and Tolerance Induction in Reconstructive Transplantation

Vascularized composite allotransplantation (VCA) is an innovative reconstructive modality for patients sustaining complex injuries not amenable to conventional treatment. Advances in immunosuppression have made VCA a clinical reality and a valid reconstructive option for such patients. The requirement, however, for multi-drug high-dose immunosuppressive regimens with their numerous side effects has hindered widespread clinical application of VCA. There is thus a need for novel immunologic modalities to minimize or even obviate the need for immunosuppression (tolerance induction) while still preserving the allograft and preventing rejection. Recent advances in targeted immunotherapy and cell-based protocols were able to achieve tolerance in selected cases of solid organ transplantation. This paved the way for innovative immunomodulatory protocols now also applied to VCA that aim for minimal immunosuppression or for induction of donor-specific tolerance. These concepts and novel protocols will be discussed in this review.

Evaluation of microvascular anastomosis using real-time, ultra-high-resolution, Fourier domain Doppler optical coherence tomography.

Background: Evolution in microsurgical techniques and tools has paved the way for supermicrosurgical anastomoses, with vessel diameters often approaching below 0.8 mm in the clinical realm and even smaller (0.2 to 0.3 mm) in murine models. Several imaging and monitoring devices have been introduced for postoperative monitoring, but intraoperative guidance, assessment, and predictability have remained limited to binocular optical microscopy and the surgeon’s experience. The authors present a high-resolution, real-time, three-dimensional imaging modality for intraoperative evaluation of luminal narrowing, thrombus formation, and flow alterations. Methods: An imaging modality that provides immediate, in-depth, high-resolution, three-dimensional structure view and flow information of the anastomosed site, called phase-resolved Doppler optical coherence tomography, was developed. Twenty-two mouse femoral artery anastomoses and 17 mouse venous anastomoses were performed and evaluated. Flow status, vessel inner lumen three-dimensional structure, and early thrombus detection were analyzed based on imaging results. Predictions formed correlated with actual long-term surgical outcomes. Eventually, four cases of mouse orthotopic limb transplantation were carried out, and predicted long-term patency based on imaging results was confirmed by actual results. Results: The assessments based on high-resolution three-dimensional visualization of the vessel flow status and inner lumen provided by phase-resolved Doppler optical coherence tomography show 92 percent sensitivity and 90 percent specificity for arterial anastomoses and 90 percent sensitivity and 86 percent specificity for venous anastomoses. Conclusions: Phase-resolved Doppler optical coherence tomography is an effective evaluation tool for microvascular anastomosis. It can predict the long-term vessel patency with high sensitivity and specificity.

Preoperative Anemia and Postoperative Outcomes in Immediate Breast Reconstructive Surgery: A Critical Analysis of 10,958 Patients from the ACS-NSQIP Database.

Background: Preoperative anemia is independently associated with adverse outcomes after general and cardiac surgery. Outcomes after breast reconstruction are not established. We assessed the effect of preoperative anemia on 30-day postoperative morbidity and length of hospital stay (LOS) in patients undergoing immediate breast reconstruction. Methods: We identified patients undergoing immediate breast reconstruction from 2008 to 2010 from the American College of Surgeons’ National Surgical Quality Improvement Program database (a prospective outcomes-based registry from hospitals worldwide). De-identified data were obtained for demographics, preoperative risk factors, 30-day morbidity, and LOS. Morbidity variables included flap/graft/prosthesis, cardiac, respiratory, neurological, urinary, wound, and venous thromboembolism outcomes. Logistic regression assessed the crude and adjusted effect of anemia (hematocrit <36%) on postoperative 30-day morbidity. Measures of central tendency of LOS were compared across increasing severities of anemia in patients developing adverse events versus controls. Results: The study population included 10,958 patients; 1556 (16.74%) had preoperative anemia. Crude odds ratio for 30-day morbidity was significantly higher in anemic patients, unadjusted odds ratio = 1.33 (P < 0.008). This prevailed after extensive adjustment for confounding, yielding an adjusted odds ratio = 1.38 (P < 0.03). Patients who experienced adverse effects had protracted LOS, and the presence of anemia significantly amplified this effect. Conclusions: These data provide new insight into the effect of anemia in immediate breast reconstruction, demonstrating an independent association between preoperative anemia and 30-day morbidity. These findings suggest treating anemia when possible; however, prospective studies should explore the efficacy, safety, and cost-effectiveness of such treatments.