Cell therapy in bone healing disorders

Abstract

In addition to osteosynthetic stabilizing techniques and autologous bone transplantations, so-called orthobiologics play an increasing role in the treatment of bone healing disorders. Besides the use of various growth factors, more and more new data suggest that cell-based therapies promote local bone regeneration. For ethical and biological reasons, clinical application of progenitor cells on the musculoskeletal system is limited to autologous, postpartum stem cells. Intraoperative one-step treatment with autologous progenitor cells, in particular, delivered promising results in preliminary clinical studies. This article provides an overview of the rationale for, and characteristics of the clinical application of cell-based therapy to treat osseous defects based on a review of existing literature and our own experience with more than 100 patients. Most clinical trials report successful bone regeneration after the application of mixed cell populations from bone marrow. The autologous application of human bone marrow cells which are not expanded ex vivo has medico-legal advantages. However, there is a lack of prospective randomized studies including controls for cell therapy for bone defects. Autologous bone marrow cell therapy seems to be a promising treatment option which may reduce the amount of bone grafting in future.

Keywords: bone defect; cell therapy; osteoblast.; stem cell.

Figure 1

The increasing frequency of publications on “donor site morbidity” and “bone” listed by Medline reflects the growing interest and examination of bone harvesting-related damage.

Figure 2

Summary of important intracellular pathways of signal transduction during osteoblastic differentiation. Cytomechanic stimuli, BMPs and inflammatory stimuli, in particular, encourage osteoblastic differentiation. The expression of some of the listed KO-factors, such as Lef1/Tcf7, decreases towards the end of osteogenic differentiation. On the other hand, other expression factors (e.g. Lef1▽N), increase in terminal osteoblastic differentiation. The differentiation paths of adipoblasts and osteoblasts from a common progenitor cell separate relatively late, whereby adipose tissue in addition to human bone marrow is suitable as the original tissue used in cell therapies for bone regeneration. Due to the small or even lack of expression of MHC-II, mesenchymal progenitor cells have a low immunogenetic potential. Moreover, in contrast to other cell types, they have an immunosuppressive effect on neighboring cells. ALK: activin receptor-like kinase; ALP: alkaline phosphatase; APC: activated protein C; BMP: bone morphogenic protein; cbfa: core binding factor; Cdk: cyclin-dependent kinases; CHOP: CCAAT enhancer-binding protein (C/EBP) homologous protein; CTGF: connective tissue growth factor; cAMP: cyclic adenosine monophosphate; COX: cyclo-oxygenase; ERK: extracellular signal-related kinase; LRP: LDL receptor-related protein; MAP: mitogen-activated protein kinase; MHC: major histocompatibility complex; OAZ: Olf-1/EBF-associated zinc finger; PG: prostaglandin(s); PPAR: peroxisome proliferator activated receptor; SF: short form; SnoN: Ski-related novel oncogene; STAT: transducer and activator of transcription; Tob: transducer of erbB2; VEGF: vascular derived growth factor; Wnt: wingless gene; sFRP: secreted frizzled related protein, Lef: lymphoid enhancer binding factor.

Figure 3

In iliac crest-vacuum aspiration, the geometry of an aspiration syringe influences the proportion of MSCs in the aspirate. The pressure required to retrieve the mesenchymal cells is exerted at the tip of the needle and is defined by the formula: pressure (P) = force (F)/area (A), whereby the force used to create a vacuum is created by withdrawing the plunger of the syringe. This force remains relatively constant. Narrow, long syringes are, therefore, advantageous when harvesting MSCs using bone marrow aspiration.

Figure 4

The areas of the iliac crest reached by the tip of the aspiration needle if inserted at diverging angles at the same point overlap, so that areas that have been perforated and aspirated once already are subjected to the procedure several times. This leads to a drop in the amount of MSCs per volume of bone marrow aspirate. If the positions of the inserted needle are parallel, then new MSC harvesting areas will always be accessed.

Figure 5

Healing course after autologous cell therapy with bone marrow aspiration concentrate (“BMAC”) augmented with HA granules in a 4-year old male patient with a large aneurysmal bone cyst of the proximal femur. Ten months after surgery, relevant new bone formation starting within the transplant is observed in computed tomography scan (star, *). The clinical and radiological 3.5 year follow up after treatment showed no recurrence and an asymptomatic patient. Based on the reduced amount of autologous bone available for grafting, pediatric patients in particular might benefit from the minimally invasive cell therapy.