Intra-articular injection of micronized dehydrated human amnion/chorion membrane attenuates osteoarthritis development

Nick J Willett, Tanushree Thote, Angela S P Lin, Shamus Moran, Yazdan Raji, Sanjay Sridaran, Hazel Y Stevens, Robert E Guldberg, Nick J Willett, Tanushree Thote, Angela S P Lin, Shamus Moran, Yazdan Raji, Sanjay Sridaran, Hazel Y Stevens, Robert E Guldberg

Abstract

Introduction: Micronized dehydrated human amnion/chorion membrane (μ-dHACM) is derived from donated human placentae and has anti-inflammatory, low immunogenic and anti-fibrotic properties. The objective of this study was to quantitatively assess the efficacy of μ-dHACM as a disease modifying intervention in a rat model of osteoarthritis (OA). It was hypothesized that intra-articular injection of μ-dHACM would attenuate OA progression.

Methods: Lewis rats underwent medial meniscal transection (MMT) surgery to induce OA. Twenty four hours post-surgery, μ-dHACM or saline was injected intra-articularly into the rat joint. Naïve rats also received μ-dHACM injections. Microstructural changes in the tibial articular cartilage were assessed using equilibrium partitioning of an ionic contrast agent (EPIC-μCT) at 21 days post-surgery. The joint was also evaluated histologically and synovial fluid was analyzed for inflammatory markers at 3 and 21 days post-surgery.

Results: There was no measured baseline effect of μ-dHACM on cartilage in naïve animals. Histological staining of treated joints showed presence of μ-dHACM in the synovium along with local hypercellularity at 3 and 21 days post-surgery. In MMT animals, development of cartilage lesions at 21 days was prevented and number of partial erosions was significantly reduced by treatment with μ-dHACM. EPIC-μCT analysis quantitatively showed that μ-dHACM reduced proteoglycan loss in MMT animals.

Conclusions: μ-dHACM is rapidly sequestered in the synovial membrane following intra-articular injection and attenuates cartilage degradation in a rat OA model. These data suggest that intra-articular delivery of μ-dHACM may have a therapeutic effect on OA development.

Figures

Figure 1
Figure 1
Representative histology images of μ-dHACM treated joints and MCP-1 data. A-H) Representative histology images of μ-dHACM treated naïve joints and saline treated naïve joints. E-H are zoomed in versions of regions of interest (black box) defined in A-D, respectively. μ-dHACM is visible at three days as fibrillar eosinophilic material, as indicated by the black arrows (E and G). Hypercellularity was observed in areas around dHACM fragments. I) MCP-1 levels in μ-dHACM treated and saline injected naïve rats. MCP-1 levels were significantly higher at three days in both saline and μ-dHACM injected groups compared to twenty-one days. The MCP-1 level at three days was significantly higher in the μ-dHACM injected joints compared to saline treated joints. **P <0.05 for MCP-1 levels at three and twenty-one days for both groups. *P <0.05 for MCP-1 levels at day three in saline injected and μ-dHACM injected joints. n = 5. MCP-1, monocte chemoattractant protein-1; μ-dHACM, micronized dehydrated human amnion/chorion membrane.
Figure 2
Figure 2
Effect of μ-dHACM on naïve tibial cartilage. A) Representative EPIC-μCT tibial articular cartilage thickness maps for μ-dHACM and saline injected samples in naïve joints. B) Average cartilage attenuation. C) Average cartilage thickness. D) Average cartilage volume measure at 21 days. No differences in cartilage parameters were observed between μ-dHACM and saline injected groups. n = 5. EPIC-μCT, equilibrium partitioning of an ionic contrast agent-micro computed tomography; μ-dHACM, micronized dehydrated human amnion/chorion membrane.
Figure 3
Figure 3
Effect of μ-dHACM on MMT joints as depicted by histology. A-D) Representative H & E stained histology images of μ-dHACM treated MMT joints and saline treated MMT joints. μ-dHACM visible at three days as fibrillar eosinophilic material as indicated by the black arrows (A and C). Hypercellularity observed in the area around dHACM fragments. E-H) Representative Safranin-O stained histology images of tibia. Black arrows indicate damaged cartilage surface (H). No damage was observed in μ-dHACM treated MMT joints (G) whereas erosions and weak staining for PGs were observed in saline treated MMT joints (H) at 21 days. MMT, medial meniscal transection; PGs, proteoglycans; μ-dHACM, micronized dehydrated human amnion/chorion membrane.
Figure 4
Figure 4
EPIC-μCT images depicting therapeutic effect of μ-dHACM in MMT joint. A) Representative image isolating erosion in MMT joint. B) Attenuation map indicating erosion on the MMT joint (Inset shows zoomed in view of erosion). C) Representative image isolating lesion in MMT joint. D) Attenuation map indicating erosion on the MMT joint (Inset shows zoomed in view of erosion). E-F) Pseudocolor attenuation map for EPIC-μCT sagittal tibial section for a saline injected (E) and dHACM injected (F) MMT joint. Red = higher attenuation values (lower PG content), green = lower attenuation values (higher PG content). Black arrows indicate focal defects. The μ-dHACM treated joints did not display lesions on the tibial articular cartilage surface. EPIC-μCT, equilibrium partitioning of an ionic contrast agent-micro computed tomography; MMT, medial meniscal transection; PG, proteoglycans; μ-dHACM, micronized dehydrated human amnion/chorion membrane.
Figure 5
Figure 5
Quantitative EPIC-μCT data depicting the therapeutic effect of μ-dHACM in MMT joints compared to controls. A) Average cartilage attenuation was significantly decreased in μ-dHACM treated MMT joints compared to saline injected MMT joints for the medial one-third tibial plateau. B) Average number of erosions was significantly decreased in μ-dHACM treated MMT joints compared to saline injected MMT joints. No lesions were observed in the μ-dHACM treated MMT joints. C) Average focal lesion volume in saline injected MMT joints.* p <0.05 and n =5. EPIC-μCT, equilibrium partitioning of an ionic contrast agent-micro computed tomography; MMT, medial meniscal transection; μ-dHACM, micronized dehydrated human amnion/chorion membrane.

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