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Background Degloving of the sole of the foot is a rare and serious injury because the heel pad cannot be replaced by similar tissue. The management is challenging and only a few cases have been reported with different treatment regimens. - Methods Here, we report on a 46-year-old female patient with complex foot trauma consisting of complete avulsion of the heel pad at the hindfoot and a soft tissue defect at the posterior aspect of the heel accompanied by rupture of the anterior tibial tendon and fractures of the talus, calcaneus and midfoot. The sole of the foot was fixed to the calcaneus with multiple temporary Kirschner wires and moist wound dressings. The anterior tibial tendon was sutured. The soft tissue defect at the posterior heel was treated with a free anterolateral thigh flap. The fractures were fixed in staged procedures. - Results At 2-year follow-up, the patient had a durable soft tissue cover over the heel with full sensation over the sole and pliable flap over the posterior aspect of the heel. The patient was able to fully bear weight and was pain free during her daily activities in comfortable, custom shoes. All fractures had healed, the talar neck fracture after one revision and bone grafting. The foot was plantigrade and stable with preserved painless but limited range of motion at the ankle, subtalar and mid-tarsal joints. - Conclusion The unique tissue at the sole of the foot can be salvaged even in cases of full degloving at the hindfoot with the simple method of anchorage with multiple temporary K-wires. Traumatic defects of the vulnerable skin at the posterior aspect of the heel requires durable coverage with free flap coverage. With staged treatment of all bone and soft tissue injuries, a favorable result can be obtained even in case of a complex foot trauma.

Bone in diabetes mellitus is characterized by an altered microarchitecture caused by abnormal metabolism of bone cells. Together with diabetic neuropathy, this is associated with serious complications including impaired bone healing culminating in complicated fractures and dislocations, especially in the lower extremities, so-called Charcot neuroarthropathy (CN). The underlying mechanisms are not yet fully understood, and treatment of CN is challenging. Several in vitro and in vivo investigations have suggested positive effects on bone regeneration by modifying biomaterials with sulfated glycosaminoglycans (sGAG). Recent findings described a beneficial effect of sGAG for bone healing in diabetic animal models compared to healthy animals. We therefore aimed at studying the effects of low- and high-sulfated hyaluronan derivatives on osteoclast markers as well as gene expression patterns of osteoclasts and osteoblasts from patients with diabetic CN compared to non-diabetic patients with arthritis at the foot and ankle. Exposure to sulfated hyaluronan (sHA) derivatives reduced the exaggerated calcium phosphate resorption as well as the expression of genes associated with bone resorption in both groups, but more pronounced in patients with CN. Moreover, sHA derivatives reduced the release of pro-inflammatory cytokines in osteoclasts of patients with CN. The effects of sHA on osteoblasts differed only marginally between patients with CN and non-diabetic patients with arthritis. These results suggest balancing effects of sHA on osteoclastic bone resorption parameters in diabetes.

Bone defects of critical size after compound fractures, infections, or tumor resections are a challenge in treatment. Particularly, this applies to bone defects in patients with impaired bone healing due to frequently occurring metabolic diseases (above all diabetes mellitus and osteoporosis), chronic inflammation, and cancer. Adjuvant therapeutic agents such as recombinant growth factors, lipid mediators, antibiotics, antiphlogistics, and proangiogenics as well as other promising anti-resorptive and anabolic molecules contribute to improving bone healing in these disorders, especially when they are released in a targeted and controlled manner during crucial bone healing phases. In this regard, the development of smart biocompatible and biostable polymers such as implant coatings, scaffolds, or particle-based materials for drug release is crucial. Innovative chemical, physico- and biochemical approaches for controlled tailor-made degradation or the stimulus-responsive release of substances from these materials, and more, are advantageous. In this review, we discuss current developments, progress, but also pitfalls and setbacks of such approaches in supporting or controlling bone healing. The focus is on the critical evaluation of recent preclinical studies investigating different carrier systems, dual- or co-delivery systems as well as triggered- or targeted delivery systems for release of a panoply of drugs.

The treatment of critical-size bone defects following complicated fractures, infections or tumor resections is a major challenge. The same applies to fractures in patients with impaired bone healing due to systemic inflammatory and metabolic diseases. Despite considerable progress in the development and establishment of new surgical techniques, the design of bone graft substitutes and imaging techniques, these scenarios still represent unresolved clinical problems. However, the development of new active substances gives cause for hope. This work discusses therapeutic approaches that influence angiogenesis or hypoxic situations in healing bone and surrounding tissue. In particular, the literature on sphingosine-1-phosphate receptor modulators and nitric oxide (NO•) donors, including bi-functional (hybrid) compounds like NO•-releasing cyclooxygenase-2 inhibitors, was critically reviewed with regard to their local and systemic mode of action.

In this third in a series of reviews on adjuvant drug-assisted bone healing, further approaches aiming at influencing the healing process are discussed. Local and systemic modulation of bone metabolism is persued with use of a number of drugs with completely different indications, which are characterized by a pleiotropic spectrum of action. These include drugs used to treat lipid disorders (HMG-CoA reductase inhibitors), hypertension (ACE inhibitors), osteoporosis (bisphosphonates), cancer (proteasome inhibitors) and others. Potential applications to enhance bone healing are discussed.

Critical-size bone defects after compound fractures, infection, or tumor resection are challenging to treat. The same is true for fractures in patients with impaired bone healing due to metabolic diseases and cancer. Despite considerable progress over the last decade in surgical techniques, material design, and dedicated imaging approaches, these scenarios represent unsolved clinical problems. The high socioeconomic burden of such conditions justifies increasing interest in novel osteoinductive drugs for adjuvant therapeutic approaches. There is an increasing body of experimental and clinical literature on potentially promising effects of growth factors, anti-resorptive, and anabolic agents. The true clinical efficacy of these, however, is discussed controversially. Therefore, we aimed to critically examine the hypothesis that targeted adjuvant therapies have the potential to enhance bone regeneration in critical-size bone defects and under systemic conditions that impair bone healing. This first approach to the topic deals with small molecule drugs and compounds that influence the immune response and inflammatory processes. In particular, literature reporting on selective cyclooxygenase-2 inhibitors has been reviewed with respect to their local and systemic mode of action and to stimulate further research on bone healing under critical conditions.

Ziel/Aim: Kritische Knochendefekte nach Trauma oder Tumorresektion sind eine klinische Herausforderung. Aktuelle Ansätze zur gezielten Unterstützung der Knochenregeneration schlagen den Einsatz von Biomaterialien vor, die mit einer artifiziellen extrazellulären Matrix (aEZM) aus Kollagen und Glykosaminoglykan-Derivaten beschichtet sind. Ziel dieses Pilotversuches war es, den Einfluss derartiger aEZM im Tiermodell zu charakterisieren. Methodik/Methods: In einen kritischen Knochendefekt im Femur adulter Ratten wurden Polycaprolacton-co-Laktid-Scaffolds implantiert, die mit Kollagen (Coll), Coll+Chondroitinsulfat (Coll/CS) oder Coll+hochsulfatierter Hyaluronsäure (Coll/s3HA) beschichtet waren. Als Negativkontrolle diente der Leerdefekt. Die Knochenneubildung und Wundheilung wurde nach 4 und 8 Wochen mittels Na[18F]F- und [18F]FDG-PET/CT beurteilt. Mittels CT wurde ein dem Defektbereich entsprechendes volume of interest definiert und der entsprechende SUVmean ermittelt. Darüber hinaus wurden die Femura ex vivo mittels µCT und histologischer Methoden charakterisiert. Ergebnisse/Results: Im Vergleich zum Leerdefekt führten die Scaffolds nach 4 Wochen zu einer erhöhten Na[18F]F-Anreicherung, was auf eine verstärkte initiale Knochenmineralisation schließen lässt. Unterschiede zwischen den verschiedenen aEZM wurden nicht beobachtet. Die im Vergleich zum Leerdefekt erhöhte [18F]FDG-Anreicherung nach 4 und 8 Wochen bei den Scaffolds weist auf eine vermehrte Zellaktivierung bzw. -proliferation in der Scaffold-Umgebung hin. Die Beschichtung mit Coll/CS resultierte nach 4 Wochen im größten SUVmean. Schlussfolgerungen/Conclusions: Die Kombination von Na[18F]F- und [18F]FDG-PET/CT gestattet die Charakterisierung der Biomaterial-unterstützten Geweberegeneration bei einem kritischen Knochendefektmodell der Ratte. Die Beschichtung mit einer aEZM aus Kollagen und Glykosaminoglykanen fördert die Knochenregeneration.

Bone healing involves a variety of different cell types and biological processes. Although certain key molecules have been identified, the molecular interactions of the healing progress are not completely understood. Moreover, a clinical routine for predicting the quality of bone healing after a fracture in an early phase is missing. This is mainly due to a lack of techniques to comprehensively screen for cytokines, growth factors and metabolites at their local site of action. Since all soluble molecules of interest are present in the fracture hematoma, its in-depth assessment could reveal potential markers for the monitoring of bone healing. Here, we describe an approach for sampling and quantification of cytokines and metabolites by using microdialysis, combined with solid phase extractions of proteins from wound fluids. By using a control group with an isolated soft tissue wound, we could reveal several bone defect-specific molecular features. In bone defect dialysates the neutrophil chemoattractants CXCL1, CXCL2 and CXCL3 were quantified with either a higher or earlier response compared to dialysate from soft tissue wound. Moreover, by analyzing downstream adaptions of the cells on protein level and focusing on early immune response, several proteins involved in the immune cell migration and activity could be identified to be specific for the bone defect group, e.g. immune modulators, proteases and their corresponding inhibitors. Additionally, the metabolite screening revealed different profiles between the bone defect group and the control group. In summary, we identified potential biomarkers to indicate imbalanced healing progress on all levels of analysis.

Wound healing of soft tissue and bone defects is a complex process in which cellular differentiation and adaption are regulated by internal and external factors, among them are many different proteins. In contrast to insights into the significance of various single proteins based on model systems, the knowledge about the processes at the actual site of wound healing is still limited. This is caused by a general lack of methods that allow sampling of extracellular factors, metabolites, and proteins in situ. Sampling of wound fluids in combination with proteomics and metabolomics is one of the promising approaches to gain comprehensive and time resolved data on effector molecules. Here, we describe an approach to sample metabolites by microdialysis and to extract proteins simultaneously by adsorption. With this approach it is possible (i) to collect, enrich, and purify proteins for a comprehensive proteome analysis; (ii) to detect more than 600 proteins in different defects including more than 100 secreted proteins, of which many proteins have previously been demonstrated to have diagnostic or predictive power for the wound healing state; and (iii) to combine continuous sampling of cytokines and metabolites and discontinuous sampling of larger proteins to gain complementary information of the same defect.