Improved cartilage regeneration by implantation of acellular biomaterials after bone marrow stimulation: a systematic review and meta-analysis of animal studies.

Veronica K Gonzales,Pieter Buma,Toin H Van Kuppevelt,Michiel W Pot,Willeke F Daamen,Rob B.M De Vries,Joanna Inthout

doi:10.7717/peerj.2243

Abstract

Microfracture surgery may be applied to treat cartilage defects. During the procedure the subchondral bone is penetrated, allowing bone marrow-derived mesenchymal stem cells to migrate towards the defect site and form new cartilage tissue. Microfracture surgery generally results in the formation of mechanically inferior fibrocartilage. As a result, this technique offers only temporary clinical improvement. Tissue engineering and regenerative medicine may improve the outcome of microfracture surgery. Filling the subchondral defect with a biomaterial may provide a template for the formation of new hyaline cartilage tissue. In this study, a systematic review and meta-analysis were performed to assess the current evidence for the efficacy of cartilage regeneration in preclinical models using acellular biomaterials implanted after marrow stimulating techniques (microfracturing and subchondral drilling) compared to the natural healing response of defects. The review aims to provide new insights into the most effective biomaterials, to provide an overview of currently existing knowledge, and to identify potential lacunae in current studies to direct future research. A comprehensive search was systematically performed in PubMed and EMBASE (via OvidSP) using search terms related to tissue engineering, cartilage and animals. Primary studies in which acellular biomaterials were implanted in osteochondral defects in the knee or ankle joint in healthy animals were included and study characteristics tabulated (283 studies out of 6,688 studies found). For studies comparing non-treated empty defects to defects containing implanted biomaterials and using semi-quantitative histology as outcome measure, the risk of bias (135 studies) was assessed and outcome data were collected for meta-analysis (151 studies). Random-effects meta-analyses were performed, using cartilage regeneration as outcome measure on an absolute 0–100% scale. Implantation of acellular biomaterials significantly improved cartilage regeneration by 15.6% compared to non-treated empty defect controls. The addition of biologics to biomaterials significantly improved cartilage regeneration by 7.6% compared to control biomaterials. No significant differences were found between biomaterials from natural or synthetic origin or between scaffolds, hydrogels and blends. No noticeable differences were found in outcome between animal models. The risk of bias assessment indicated poor reporting for the majority of studies, impeding an assessment of the actual risk of bias. In conclusion, implantation of biomaterials in osteochondral defects improves cartilage regeneration compared to natural healing, which is further improved by the incorporation of biologics.

Highlights

Articular cartilage is a specialized tissue that covers joint surfaces and provides a low-friction and load-bearing surface for a smooth motion of joints
The latter strategy, known as bone marrow stimulation, is relatively simple, minimally invasive and inexpensive. During this procedure the subchondral bone plate below the cartilage lesion is perforated to initiate bleeding and induce a reparative response. The principle behind this regenerative resurfacing strategy is the migration of non-differentiated bone marrow-derived multipotent stem cells from the subchondral bone into the defect site leading to the formation of new cartilage tissue (Buma et al, 2003; De Mulder et al, 2014; Erggelet et al, 2009)
Screening articles by full-text and subsequently selection for studies with empty defect controls as well as semi-quantitative histology as outcome measure resulted in 283 included studies after full-text assessment, of which 151 and 135 articles could be used for the meta-analysis and risk of bias assessment, respectively (Fig. 2)

Summary

Introduction

Articular cartilage is a specialized tissue that covers joint surfaces and provides a low-friction and load-bearing surface for a smooth motion of joints. The surgical options to treat patients with a localized cartilage defect are limited to cartilage regeneration approaches such as autologous chondrocyte implantation and microfracture surgery (Aulin et al, 2013; Bal et al, 2010). The latter strategy, known as bone marrow stimulation, is relatively simple, minimally invasive and inexpensive. During this procedure the subchondral bone plate below the cartilage lesion is perforated to initiate bleeding and induce a reparative response. The need for regeneration of more durable cartilage tissue persists

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