Patient Safety and Quality Improvement Initiatives in Cleft Lip and Palate Surgery: A Systematic Review.

BACKGROUND: Cleft lip and/or palate repair techniques require continued reevaluation of best practice through high-quality evidence. The objective of this systematic review was to highlight the existing evidence for patient safety and quality improvement (QI) initiatives in cleft lip and palate surgery. METHODS: A systematic review of published literature evaluating patient safety and QI in patients with cleft lip and/or palate was conducted from database inception to June 9, 2022, using Preferred Reporting Items for Systematic Reviews guidelines. Quality appraisal of included studies was conducted using Methodological Index for Non-Randomized Studies, Cochrane, or a Measurement Tool to Assess Systematic Reviews (AMSTAR) 2 instruments, according to study type. RESULTS: Sixty-one studies met inclusion criteria, with most published between 2010 and 2020 (63.9%). Randomized controlled trials represented the most common study design (37.7%). Half of all included studies were related to the topic of pain and analgesia, with many supporting the use of infraorbital nerve block using 0.25% bupivacaine. The second most common intervention examined was use of perioperative antibiotics in reducing fistula and infection (11.5%). Other studies examined optimal age and closure material for cleft lip repair, early recovery after surgery protocols, interventions to reduce blood loss, and safety of outpatient surgery. CONCLUSIONS: Patient safety and QI studies in cleft surgery were of moderate quality overall and covered a wide range of interventions. To further enhance PS in cleft repair, more high-quality research in the areas of perioperative pharmaceutical usage, appropriate wound closure materials, and optimal surgical timing are needed.

Effect of increasing mineralization on pre-osteoblast response to native collagen fibril scaffolds for bone tissue repair and regeneration.

With limited availability of auto- and allografts, there is increasing demand for alternative bone repair and regeneration materials. Inspired by a mimetic approach, the utility of producing engineered native protein scaffolds is being increasingly realized, demonstrating the need for continued research in this field. In previous work, we detailed a process for producing mineralized collagen scaffolds using tendon to create collagen templates of highly aligned, natively crosslinked collagen fibrils. The process produced mineral phase closely matching that of native bone, and integration of mineral with the collagen template was demonstrated to be easily controlled, allowing scaffolds to be mechanically tuned. In the current study, we have extended this work to investigate how variation in the mineralization level of these scaffolds affects the osteogenic response of pre-osteoblastic cells. Scaffolds were produced under three treatment groups, where collagen templates underwent 0, 5, or 20 mineralization cycles. Scaffolds in each treatment group were cultured with MC3T3-E1 cells for 1, 7, or 14 days. Morphologic assessment under SEM indicated decreased attachment to the mineralized scaffolds, supported by DNA results showing a significant drop between culture days 1 and 7 for mineralized scaffolds only. For adherent cells, increasing scaffold mineralization also delayed cell spreading. While mineralization presented a barrier to cell coverage of scaffolds, it increased osteogenic activity, with cells on the mineralized scaffolds showing significantly greater alkaline phosphatase activity and osteocalcin production. Understanding how increasing collagen mineralization effects pre-osteoblast function may enable design of more advanced mineralized collagen scaffolds for bone repair and regeneration.

Alternate soaking enables easy control of mineralized collagen scaffold mechanics from nano- to macro-scale.

The mechanical properties of biologic scaffolds are critical to cellular interactions and hence functional response within the body. In the case of scaffolds for bone tissue regeneration, engineered scaffolds created by combining collagen with inorganic mineral are increasingly being explored, due to their favourable structural and chemical characteristics. Development of a method for controlling the mechanics of these scaffolds could lead to significant additional advantages by harnessing the intrinsic mechnotransduction pathways of stem cells via appropriate control of scaffold mechanical properties. Here we present a method for controlling the macroscale flexural modulus of mineralized collagen sheets, and the radial indentation modulus of the sheets' constituent collagen fibrils. Scaffolds were created starting with sheets of highly aligned, natively structured collagen fibrils, prepared via cryosectioning of decellularized tendon. Sheets underwent an alternate soaking mineralization procedure, with sequential exposure to citrate-doped calcium and carbonate-containing phosphate solutions, both of which included poly aspartic acid. The extent of scaffold mineralization was controlled via number of repeated mineralization cycles: 0 (unmineralized), 5, 10, and 20 cycles were trialed. Following scaffold preparation, ultrastructure, macroscale flexural modulus, and nanoscale indentation modulus were assessed. Surface architecture studied by SEM, and inspection of individual extracted fibrils by TEM and AFM confirmed that fibrils became increasingly laden with mineral as the number of mineralization cycles increased. Measurements of collagen fibril nanomechanics using AFM showed that the radial modulus of collagen fibrils increased linearly with mineralization cycles completed, from 215 ± 125 MPa for fibrils from unmineralized (0 cycle) scaffolds to 778 ± 302 MPa for fibrils from the 20 mineralization cycle scaffolds. Measurements of scaffold macromechanics via flexural testing also showed a linear increase in flexural modulus with increasing number of mineralization cycles completed, from 18 ± 7 MPa for the 5 cycle scaffolds to 156 ± 50 MPa for the 20 cycle scaffolds. The process detailed herein provides a way to create mineralized collagen scaffolds with easily controllable mechanical properties.

Use of tendon to produce decellularized sheets of mineralized collagen fibrils for bone tissue repair and regeneration.

With demand for alternatives to autograft and allograft materials continuing to rise, development of new scaffolds for bone tissue repair and regeneration remains of significant interest. Engineered collagen-calcium phosphate (CaP) constructs can offer desirable attributes, including absence of foreign body response and possession of inherent osteogenic potential. Despite their promise, current collagen-CaP constructs are limited to nonload-bearing applications. In this article, we describe a process for creating decellularized sheets of highly aligned, natively cross-linked, and mineralized collagen fibrils, which may be useful for developing multilaminate collagen-CaP constructs with improved mechanical properties. Decellularized bovine tendons were cryosectioned to produce thin sheets of aligned collagen fibrils. Mineralization of the sheets was then performed using an alternate soaking method incorporating a polymer-induced liquid precursor (PILP) process to promote intrafibrillar mineralization, along with incorporation of physiologically relevant amounts of citrate, Mg, and carbonate. Characteristics of the produced scaffolds were assessed using energy-dispersive X-ray spectroscopy (EDX), scanning electron microscopy (SEM), and transmission electron microscopy (TEM). Scaffolds were also compared with both native bovine cortical bone and pure hydroxyapatite using X-ray powder diffraction (XRD), and Fourier transform infrared spectroscopy attenuated total reflection (FTIR-ATR). Structural and chemical analyses show that the scaffold preparation process that we described is successful in creating mineralized collagen sheets, possessing a mineral phase similar to that found in bone as well as a close association between collagen fibrils and mineral plates.

A multi-targeted approach to suppress tumor-promoting inflammation.

Cancers harbor significant genetic heterogeneity and patterns of relapse following many therapies are due to evolved resistance to treatment. While efforts have been made to combine targeted therapies, significant levels of toxicity have stymied efforts to effectively treat cancer with multi-drug combinations using currently approved therapeutics. We discuss the relationship between tumor-promoting inflammation and cancer as part of a larger effort to develop a broad-spectrum therapeutic approach aimed at a wide range of targets to address this heterogeneity. Specifically, macrophage migration inhibitory factor, cyclooxygenase-2, transcription factor nuclear factor-κB, tumor necrosis factor alpha, inducible nitric oxide synthase, protein kinase B, and CXC chemokines are reviewed as important antiinflammatory targets while curcumin, resveratrol, epigallocatechin gallate, genistein, lycopene, and anthocyanins are reviewed as low-cost, low toxicity means by which these targets might all be reached simultaneously. Future translational work will need to assess the resulting synergies of rationally designed antiinflammatory mixtures (employing low-toxicity constituents), and then combine this with similar approaches targeting the most important pathways across the range of cancer hallmark phenotypes.