Allometrically scaling tissue forces drive pathological foreign-body responses to implants via Rac2-activated myeloid cells.

Small animals do not replicate the severity of the human foreign-body response (FBR) to implants. Here we show that the FBR can be driven by forces generated at the implant surface that, owing to allometric scaling, increase exponentially with body size. We found that the human FBR is mediated by immune-cell-specific RAC2 mechanotransduction signalling, independently of the chemistry and mechanical properties of the implant, and that a pathological FBR that is human-like at the molecular, cellular and tissue levels can be induced in mice via the application of human-tissue-scale forces through a vibrating silicone implant. FBRs to such elevated extrinsic forces in the mice were also mediated by the activation of Rac2 signalling in a subpopulation of mechanoresponsive myeloid cells, which could be substantially reduced via the pharmacological or genetic inhibition of Rac2. Our findings provide an explanation for the stark differences in FBRs observed in small animals and humans, and have implications for the design and safety of implantable devices.

Computer-assisted planning and patient-specific plates in orthognathic surgery: a global study.

OBJECTIVE: Using computer-assisted surgery (CAS) and patient-specific plates (PSP) in orthognathic surgery has shown improved accuracy and efficiency compared with traditional techniques. This study analyzed current global trends in planning and investigated the reasons for CAS and PSP use. STUDY DESIGN: A survey of 29 multiple choice questions was distributed to AO Foundation Craniomaxillofacial e-mail subscribers biweekly between July 14, 2021 and September 2, 2021. Questions focused on specifics of respondents' preoperative workup, methods of data collection, and the use of cutting guides and patient-specific plates. Objective clinical outcomes and subjective surgeon reasons for use were also investigated. RESULTS: Of the 557 responses, 420 (75.4%) participant responses were eligible for analyses. Most (302/420, 71.9%) respondents used CAS when performing orthognathic surgery, although regional differences were observed. Almost all respondents in North America implemented CAS in their surgery plan (44/46, 95.7%) compared with only 47.4% (18/38) in the Middle East/North Africa. Surgeons with 10 to 15 years of experience were far more likely to incorporate CAS. More than half (175/301, 58.1%) of CAS users also used PSP, of which 43% (68/158) did so for maxillary-only cases, 3.2% (5/158) used PSP for mandible-only surgeries, and 42.4% (67/158) used PSP for both. Surgeons' primary reasons for using CAS and PSP were accuracy (200/253, 79.1%), efficiency (196/253, 77.5%), and ease of preoperative planning (150/253, 59.3%). Most (77.9%) surgeons perceived that CAS was equal to or faster than traditional surgery. CONCLUSIONS: Our study shows differences in use regionally and with surgeon experience. Surgeons primarily use CAS and PSP in orthognathic surgery to increase accuracy and efficiency, minimize intraoperative deviations from the surgical plan, and reduce total surgical time.

Reconstruction of Bilateral Mandibular Condyles Using a Single Vascularized Fibula.

Patients with end-stage temporomandibular joint (TMJ) pathology present with loss of vertical ramus height with resulting retrognathia, anterior open bite, and restricted jaw function requiring joint reconstruction. Costochondral grafts, long considered the gold standard for TMJ reconstruction, carry risks of bony ankylosis and resorption. Custom-made alloplastic TMJ prostheses show excellent objective and subjective outcomes but are also associated with complications such as infection or metal sensitivity, and necessitate hardware explantation in some cases. Revision surgeries are rare but present a real challenge. We present the case of a 50-year-old woman with longstanding TMJ arthritis, having undergone many surgical procedures to her TMJ, including explantation of failed alloplastic replacement, who presented with bilateral facial weakness as well as difficulty chewing and swallowing food. She had class II malocclusion with retrodisplacement of her mandible and anterior open bite, and moderate trismus with an inter-incisal opening of only 15 mm, consistent with fibrous ankylosis. After weighing all the reconstructive options, bilateral mandibular condyle and ramus reconstruction with a single fibula free flap (FFF) was planned with the use of preoperative virtual surgical planning (VSP) and 3D-printing of osteotomy and repositioning guides. A 2-team approach increases efficiency of the procedure and decreases operative time. The procedure and postoperative recovery were uncomplicated, and at her 2-month follow-up, she had increased range of motion and maintained the planned position of her mandible. Her masticatory function and deglutition were also improved due to the correction of her malocclusion and repair of her anterior open bite.

Subtotal Mandible Reconstruction with a Free Fibula Flap and No Skin Incisions.

Resection of large mandibular tumors followed by primary reconstruction using free tissue transfer is typically accomplished using transcutaneous cervical incisions, which provide access for ablation as well as inset of the osseous free flap. This approach offers wide exposure; however, it subjects the patient to potential facial scarring, marginal mandibular nerve injury, lip deformity/incompetence, formation of orocutaneous fistulae, as well as functional impairments to speech, mastication, and deglutition. To reduce morbidity and to preserve aesthetics, a transoral approach can be used in cases that do not require a neck dissection. This technique can be coupled with transoral dissection of the facial vessels for intraoral microanastomoses to avoid extraoral incisions altogether. We present a case of a large 17.2 cm subtotal mandibulectomy and 3-segment fibular free flap reconstruction using virtual surgical planning, with patient-specific cutting guides and reconstruction plate performed entirely transorally without any skin incisions. Although technically challenging, this is a safe and effective technique for large segmental mandibular defects, which provides superior cosmetic and functional outcomes.

Beneath the Surface: A Review of Laser Remodeling of Hypertrophic Scars and Burns.

Significance: Hypertrophic scars, keloids, and burn injuries of the skin have a significant impact on patients' lives and impact the health care system tremendously. Treating skin wounds and lesions can be challenging, with a variety of choices available for treatment. Scar and burn managements range from invasive, surgical options such as scar excision to less invasive, nonsurgical alternatives such as laser therapy or topical drug application. Recent Advances: Laser treatment has become increasingly popular, with a growing body of research supporting its use for scars and burns. Numerous methods are available for the treatment of these skin diseases, including different nonsurgical laser therapies. Critical Issues: To date, the optimal treatment method for scars, keloids, and burn injuries of the skin has not yet been established, although it is an area of increasing clinical concern. Future Directions: This review provides an updated summary of the treatment of scars and burn wounds of the skin using different laser treatments, including the most recent technologies. It addresses their indications, mechanisms of action, differences, efficacies, and complications.

Optimization of transdermal deferoxamine leads to enhanced efficacy in healing skin wounds.

Chronic wounds remain a significant burden to both the healthcare system and individual patients, indicating an urgent need for new interventions. Deferoxamine (DFO), an iron-chelating agent clinically used to treat iron toxicity, has been shown to reduce oxidative stress and increase hypoxia-inducible factor-1 alpha (HIF-1α) activation, thereby promoting neovascularization and enhancing regeneration in chronic wounds. However due to its short half-life and adverse side effects associated with systemic absorption, there is a pressing need for targeted DFO delivery. We recently published a preclinical proof of concept drug delivery system (TDDS) which showed that transdermally applied DFO is effective in improving chronic wound healing. Here we present an enhanced TDDS (eTDDS) comprised exclusively of FDA-compliant constituents to optimize drug release and expedite clinical translation. We evaluate the eTDDS to the original TDDS and compare this with other commonly used delivery methods including DFO drip-on and polymer spray applications. The eTDDS displayed excellent physicochemical characteristics and markedly improved DFO delivery into human skin when compared to other topical application techniques. We demonstrate an accelerated wound healing response with the eTDDS treatment resulting in significantly increased wound vascularity, dermal thickness, collagen deposition and tensile strength. Together, these findings highlight the immediate clinical potential of DFO eTDDS to treating diabetic wounds. Further, the topical drug delivery platform has important implications for targeted pharmacologic therapy of a wide range of cutaneous diseases.

Acceleration of Diabetic Wound Healing with PHD2- and miR-210-Targeting Oligonucleotides.

In diabetes-associated chronic wounds, the normal response to hypoxia is impaired and many cellular processes involved in wound healing are hindered. Central to the hypoxia response is hypoxia-inducible factor-1α (HIF-1α), which activates multiple factors that enhance wound healing by promoting cellular motility and proliferation, new vessel formation, and re-epithelialization. Prolyl hydroxylase domain-containing protein 2 (PHD2) regulates HIF-1α activity by targeting it for degradation under normoxia. HIF-1α also upregulates microRNA miR-210, which in turn regulates proteins involved in cell cycle control, DNA repair, and mitochondrial respiration in ways that are antagonistic to wound repair. We have identified a highly potent short synthetic hairpin RNA (sshRNA) that inhibits expression of PHD2 and an antisense oligonucleotide (antimiR) that inhibits miR-210. Both oligonucleotides were chemically modified for improved biostability and to mitigate potential immunostimulatory effects. Using the sshRNA to silence PHD2 transcripts stabilizes HIF-1α and, in combination with the antimiR targeting miR-210, increases proliferation and migration of keratinocytes in vitro. To assess activity and delivery in an impaired wound healing model in diabetic mice, PHD2-targeting sshRNAs and miR-210 antimiRs both alone and in combination were formulated for local delivery to wounds using layer-by-layer (LbL) technology. LbL nanofabrication was applied to incorporate sshRNA into a thin polymer coating on a Tegaderm mesh. This coating gradually degrades under physiological conditions, releasing sshRNA and antimiR for sustained cellular uptake. Formulated treatments were applied directly to splinted full-thickness excisional wounds in db/db mice. Cellular uptake was confirmed using fluorescent sshRNA. Wounds treated with a single application of PHD2 sshRNA or antimiR-210 closed 4 days faster than untreated wounds, and wounds treated with both oligonucleotides closed on average 4.75 days faster. Markers for neovascularization and cell proliferation (CD31 and Ki67, respectively) were increased in the wound area following treatment, and vascular endothelial growth factor (VEGF) was increased in sshRNA-treated wounds. Our results suggest that silencing of PHD2 and miR-210 either together or separately by localized delivery of sshRNAs and antimiRs is a promising approach for the treatment of chronic wounds, with the potential for rapid clinical translation.

Deferoxamine can prevent pressure ulcers and accelerate healing in aged mice.

Chronic wounds are a significant medical and economic problem worldwide. Individuals over the age of 65 are particularly vulnerable to pressure ulcers and impaired wound healing. With this demographic growing rapidly, there is a need for effective treatments. We have previously demonstrated that defective hypoxia signaling through destabilization of the master hypoxia-inducible factor 1α (HIF-1α) underlies impairments in both aging and diabetic wound healing. To stabilize HIF-1α, we developed a transdermal delivery system of the Food and Drug Administration-approved small molecule deferoxamine (DFO) and found that transdermal DFO could both prevent and treat ulcers in diabetic mice. Here, we demonstrate that transdermal DFO can similarly prevent pressure ulcers and normalize aged wound healing. Enhanced wound healing by DFO is brought about by stabilization of HIF-1α and improvements in neovascularization. Transdermal DFO can be rapidly translated into the clinic and may represent a new approach to prevent and treat pressure ulcers in aged patients.