Mechanisms of fracture healing
A fracture healing disorder or delayed fracture healing ("delayed union") is present if a fracture has not bridged the bone after four months. If there is no fracture healing even after six months, this is referred to as pseudarthrosis ("non-union").
There are many reasons for delayed or non-healing of fractures. The most common reasons are
Our research group is therefore investigating the causes of fracture healing disorders and pseudarthrosis in a clinical context and in animal models. The aim is to gain a better understanding of fracture healing disorders in order to identify patients at risk at an early stage and develop new therapies.
In our current project, we are investigating whether bone lengthening can be performed more quickly after major bone loss by means of callus distraction. Although callus distraction has been established for a long time and despite the constant development of new implants, the duration of treatment in patients can be months to years, as a suitable distraction speed of approx. 1 mm per day has been assumed up to now. Therefore, our aim is to investigate the optimal distraction speed at the beginning and at the end of the distraction phase in the rat model. The groups differ in terms of transport speed (constant speed vs. first fast, then slow vs. first slow, then fast). Using radiological (X-ray, μ-CT scans), histological (acrylate histology) and molecular biological (qRT-PCR, Western blot) methods, the regeneration quality is then examined at four different time points.
Influence of polytrauma on the musculoskeletal system
In medicine, a polytrauma is defined as several simultaneous injuries to different parts of the body, one of which or a combination of which is life-threatening (definition according to Prof. Dr. med. Harald Tscherne). In Germany, polytrauma is mainly caused by traffic accidents and accidents at work or during leisure time. Furthermore, the severely injured patients in 70% cases are predominantly male and on average around 40 years old. However, the proportion of patients over the age of 70 has risen continuously over the last 10 years.
By improving the preclinical and clinical care of severely injured patients (e.g. shock room care according to Advanced Trauma Life Support®), it has been possible to significantly reduce mortality in recent decades. Nevertheless, polytrauma is still the most common cause of death under the age of 45. According to the German Society for Trauma Surgery (DGU), one in eight seriously injured people dies. Accordingly, from a socio-economic perspective, accident-related deaths are more relevant than malignant neoplasms or cardiovascular diseases, as they are associated with a greater loss of years of life. Around half of the patients who die succumb to their injuries in the first 24 hours after the accident as a result of severe craniocerebral trauma or unstoppable bleeding. The remaining 50 % die in the further clinical course from multi-organ failure or generalized infection (sepsis). Both clinical pictures are based on a complex inflammatory reaction of the entire organism.
Furthermore, complications in fracture healing after polytrauma occur significantly more frequently compared to patients who have only suffered an isolated fracture. The average hospital stay of 3 weeks is followed by a long phase of health, social and occupational rehabilitation, so that complete reintegration of severely injured patients is only achieved on average 49 weeks after the original accident. Our working group is therefore investigating the underlying mechanisms after polytrauma in order to understand these and subsequently be able to positively influence them for better and faster healing and reintegration of our patients. The current focus is on investigating the influence of polytrauma on the bone, muscle and gastrointestinal tract using a long-term mouse model.
Regeneration after trauma
Another challenge in trauma surgery is the healing of larger bone defects and the treatment of cartilage damage. The tissue replacement of destroyed musculoskeletal tissue with human mesenchymal stem cells from the bone marrow represents a promising therapeutic option in the context of regenerative medicine. However, these cells exhibit strong donor-dependent differences that can have a major impact on the success of stem cell-based therapy. These differences can be found in particular in the ability of the stem cells to form cartilage (chondrogenic differentiation) and bone (osteogenic differentiation).
It is interesting to find out what causes these patient-dependent differences. Are the properties of the stem cells influenced by the patient's age, gender, lifestyle or (pre-)illnesses? We have already conducted studies on the influence of age, gender and BMI of bone marrow donors (Zong, Q. et al. Cell Transplant. 2024; Selle, M. et al. Bone. 2021). We used a collection of cryopreserved bone marrow-derived mesenchymal stem cells. The bone marrow came from voluntary donors at our clinic who, after detailed information, consented to bone marrow donation under anesthesia by means of iliac crest puncture during an upcoming routine operation. The mesenchymal stem cells were isolated in our laboratory under standardized conditions immediately after bone marrow aspiration and subsequently characterized by examining the self-renewal potential of the cells (colony-forming unit assay), the expression of surface antigens (flow cytometry) and the differentiability of the cells in the adipogenic, chondrogenic and osteogenic direction. Furthermore, differentiated anonymized donor data was collected in a database (age, gender, height, weight, reason for hospitalization, concomitant diseases, medications taken, a small pre-operative blood count, smoking status, alcohol consumption, diet, BMI and information on sporting activity).
In the future, we would like to use these cells to test the colonization of new innovative implants and novel materials and look forward to interesting cooperation requests.
Publications (selection)
Jiang Z, Clausen JD, Jahn D, Wulsten D, Gladitz LM, Bundkirchen K, Krettek C, Neunaber C. Ex vivo storage of human osteochondral allografts: Long-term analysis over 300 days using a Ringer-based solution. J Orthop Res. 2024 Mar 5.
Zhou Y, Meng F, Köhler K, Bülow JM, Wagner A, Neunaber C, Bundkirchen K, Relja B. Age-related exacerbation of lung damage after trauma is associated with increased expression of inflammasome components. Front Immunol. 2024 Jan 11;14:1253637.
Zong Q, Bundkirchen K, Neunaber C, Noack S. Effect of High BMI on Human Bone Marrow-Derived Mesenchymal Stromal Cells. Cell Transplant. 2024 Jan- Dec;33:9636897241226546.
Meng F, Zhou Y, Wagner A, Bülow JM, Köhler K, Neunaber C, Bundkirchen K, Relja B. Impact of age on liver damage, inflammation, and molecular signaling pathways in response to femoral fracture and hemorrhage. Front Immunol. 2023 Aug 24;14:1239145.
Zong Q, Bundkirchen K, Neunaber C, Noack S. Are the Properties of Bone Marrow-Derived Mesenchymal Stem Cells Influenced by Overweight and Obesity? Int J Mol Sci. 2023 Mar 2;24(5):4831.
Westerkowsky EK, Soares de Almeida AM, Selle M, Harms O, Bundkirchen K, Neunaber C, Noack S. Characterization of Human, Ovine and Porcine Mesenchymal Stem Cells from Bone Marrow: Critical In Vitro Comparison with Regard to Humans. Life (Basel). 2023 Mar 6;13(3):718
Örgel M, Elareibi M, Graulich T, Krettek C, Neunaber C, Aschoff HH, Ranker A, Winkelmann M. Osseoperception in transcutaneous osseointegrated prosthetic systems (TOPS) after transfemoral amputation: a prospective study. Arch Orthop Trauma Surg. 2023 Feb;143(2):603-610.
Bundkirchen K, Ye W, Nowak AJ, Lienenklaus S, Welke B, Relja B, Neunaber C. Fracture Healing in Elderly Mice and the Effect of an Additional Severe Blood Loss: A Radiographic and Biomechanical Murine Study. Bioengineering (Basel). 2023 Jan 5;10(1):70.
Haag F, Janicova A, Xu B, Powerski M, Fachet M, Bundkirchen K, Neunaber C, Marzi I, Relja B, Sturm R. Reduced phagocytosis, ROS production and enhanced apoptosis of leukocytes upon alcohol drinking in healthy volunteers. Eur J Trauma Emerg Surg. 2022 Aug;48(4):2689-2699.
He Y, Omar M, Feng X, Neunaber C, Jagodzinski M. Impact of smoking on the incidence and post-operative complications of total knee arthroplasty: A systematic review and meta-analysis of cohort studies. Bosn J Basic Med Sci. 2022 Jun 1;22(3):353-365.
Noack L, Bundkirchen K, Xu B, Gylstorff S, Zhou Y, Köhler K, Jantaree P, Neunaber C, Nowak AJ, Relja B. Acute Intoxication With Alcohol Reduces Trauma- Induced Proinflammatory Response and Barrier Breakdown in the Lung via the Wnt/β-Catenin Signaling Pathway. Front Immunol. 2022 May 18;13:866925.
Selle M, Koch JD, Ongsiek A, Ulbrich L, Ye W, Jiang Z, Krettek C, Neunaber C, Noack S. Influence of age on stem cells depends on the sex of the bone marrow donor. J Cell Mol Med. 2022 Mar;26(5):1594-1605. doi: 10.1111/jcmm.17201. Epub 2022 Jan 27.
Örgel M, Zimmer G, Graulich T, Gräff P, Macke C, Krettek C, Winkelmann M, Neunaber C. The impact of lifestyle on forearm fractures in children: A retrospective cohort analysis. Bone. 2021 Dec;153:116149.
Long Y, Bundkirchen K, Gräff P, Krettek C, Noack S, Neunaber C. Cytological Effects of Serum Isolated from Polytraumatized Patients on Human Bone Marrow- Derived Mesenchymal Stem Cells. Stem Cells Int. 2021 Nov 28;2021:2612480.
Homeier JM, Bundkirchen K, Winkelmann M, Graulich T, Relja B, Neunaber C, Macke C. Selective Inhibition of IL-6 Trans-Signaling Has No Beneficial Effect on the Posttraumatic Cytokine Release after Multiple Trauma in Mice. Life (Basel). 2021 Nov 17;11(11):1252.
Schrodi V, Neunaber C, Bundkirchen K, Ye W, Jiang Z, Petri M, Krettek C, Noack S. Characteristics of Mesenchymal Stem Cells Are Independent of Bone Marrow Storage Temperatures. Stem Cells Int. 2021 Oct 19;2021:6864988.
Leditzke K, Wagner MEH, Neunaber C, Clausen JD, Winkelmann M. Neutrophil Gelatinase-associated Lipocalin Predicts Post-traumatic Acute Kidney Injury in Severely Injured Patients. In Vivo. 2021 Sep-Oct;35(5):2755-2762.
Zeller AN, Selle M, Gong Z, Winkelmann M, Krettek C, Bundkirchen K, Neunaber C, Noack S. Osteoporosis is accompanied by reduced CD274 expression in human bone marrow-derived mesenchymal stem cells. Eur Cell Mater. 2021 May 31;41:603-615.
Relja B, Yang B, Bundkirchen K, Xu B, Köhler K, Neunaber C. Different experimental multiple trauma models induce comparable inflammation and organ injury. Sci Rep. 2020 Nov 19;10(1):20185.
Hensel N, Brickwedde H, Tsaknakis K, Grages A, Braunschweig L, Lüders KA, Lorenz HM, Lippross S, Walter LM, Tavassol F, Lienenklaus S, Neunaber C, Claus P, Hell AK. Altered bone development with impaired cartilage formation precedes neuromuscular symptoms in spinal muscular atrophy. Hum Mol Genet. 2020 Sep 29;29(16):2662-2673.
Laboratory equipment:
Fully equipped small animal OR with Kubtec 2D Parameter X-ray/DXA Cabinet, histology lab for calcified and decalcified samples, Precellys 24 Homogenizer, Eppendorf Concentrator Plus, BioTek Epoch Microplate Reader, StepOne qRT-PCR,Vilber Fusion Fx Western Blot Analyzer, Attune Flow Cytometer NxT, Keyence digital 4K Microscope VHX7000, Olympus BX41 microscope, Olympus CKX41 fluorescence microscope, fully equipped cell culture
Prof. Dr. Claudia Neunaber
+49 511 532 2929
Neunaber.Claudia(at)mh-hannover.de
NIFE
Stadtfelddamm 34
30625 Hanover