黏性補充劑與胜肽交聯劑回復退化性椎間盤生物力學功能之可行性研究

Abstract

椎間盤為人體內負責承重與吸收衝擊的主要器官，椎間盤退化疾病將不可避免地降低患者生活品質，是人口高齡化社會所必須正視的醫療問題。椎間盤的功能表現取決於其固體結構機械性質以及液體流動機制，可由靜態流變性質與動態力學性質加以評估。深入了解影響椎間盤靜態流變性質與動態力學性質的各種機制，將有助於增進前瞻性退化性椎間盤治療方法的效益。本研究的第一部份，探討不同負載條件以及退化程度對椎間盤靜態流變性質的影響，探討的流變參數分別代表椎間盤於靜態負載時，整體勁度與內部液體流動性。實驗結果顯示：於潛變期間，椎間盤勁度增加，液體流動性降低；於鬆弛期間，椎間盤勁度降低，液體流動性不變；當負載力量增加，椎間盤勁度上升而液體流動性下降；疲勞負載時間越長，椎間盤勁度不變，但液體流動性降低；隨著退化程度增加，椎間盤勁度升高，液體流動性降低。本研究結果另可推論椎間盤勁度與含水量為負向相關，液體滲透度與椎間盤孔隙度為正向相關。 本研究的第二部份以胰蛋白脢降解椎間核模擬退化初期的椎間盤，比較黏性補充劑(玻尿酸)與胜肽交聯劑(梔子素)對於回復退化椎間盤的細部結構性質與整體動態力學性質的效益，並分析椎間盤細部結構性質對整體動態力學性質的影響程度。實驗中所探討的椎間盤細部結構性質包含椎間核含水量、椎間核黏彈性、椎間環結構完整性；椎間盤動態力學性質包含椎間盤受衝擊負載時，整體勁度與能量緩衝性。結果顯示：玻尿酸可回復退化椎間核的含水量，提升退化椎間盤於疲勞負載後的能量緩衝性；梔子素可回復退化椎間核的含水量，提升退化椎間核的彈性、聚合剥離的椎間環纖維，回復退化椎間盤於疲勞負載後的能量緩衝性。玻尿酸與梔子素皆無法改變退化椎間核的黏性與椎間盤於疲勞負載後的勁度。與玻尿酸相較之下，梔子素較能回復退化性椎間盤的結構性質與生物力學功能，但梔子素會將水分限制於椎間核內，使水分無法隨疲勞負載而外流，並改變椎間盤動態性質在疲勞負載下的變化趨勢，因此梔子素本身在回復退化性椎間盤生物力學功能上的可行性並不高。在椎間盤細部結構性質與整體動態力學性質的迴歸分析上，結果顯示椎間核彈性對椎間盤疲勞負載前的勁度有較大的相關性，椎間核黏性對椎間盤疲勞負載後的能量緩衝性有較大的相關性。 本論文推測椎間盤流變性質受負載條件與退化程度而改變的機制在於含水量與椎間盤內部孔徑的變化，當退化產生時，椎間盤勁度升高且內部水分的流通性降低。黏性補充劑與胜肽交聯劑皆無法完全回復退化椎間盤的生物力學功能，因此在未來的研究裡，仍需繼續尋找合適的生物性相容材料，以應用於退化性椎間盤疾病的治療策略上。

The major biomechanical functions of intervertebral disc are to resist the external load and to dissipate the shock energy imposed on the human body during daily activities. The disc functions depend on the internal fluid dynamics and compositional integrity of disc matrix. The clarifications of effect of loading conditions and degenerations on the biomechanical functions of disc will improve the treatment efficacy for the degenerated disc diseases. Two biomechanical models, i.e., rheological model and the dynamic model, have been used to simulate the disc medium term and short term behaviors. The rheological model is traditionally described by a linear biphasic theory model, and the dynamic model is described by a 1-D spring and dashpot model. The rheological and dynamic properties derived from the both models can indicate the disc stiffness and internal fluid flow capability of disc matrix and different time scale. The first part of this dissertation studied the effect of loading history, loading magnitude, fatigue loading and degeneration on the disc rheology. The results showed that the disc stiffness increased and the fluid flow capability decreased during the creep loading, the disc stiffness decreased and the fluid flow capability unchanged during the relaxation loading. The disc stiffness increased and the fluid flow capability decreased with the loading magnitude. After the fatigue loading time, the disc stiffness unchanged but the fluid flow capability decreased. The degeneration increased the disc stiffness but decreased the fluid flow capability. The results suggested that the disc stiffness was negatively related to the disc hydration level, and the fluid flow capability was positively related to the matrix pore size. In the second part of this study, the recovery efficiency of viscosupplement (i.e., hyaluronic acid) and crosslinker (i.e., genipin) on the degenerated disc was evaluated by changes of the water content and viscoelasticity of nucleus pulposus, structural integrity of the anular fibrosus, and dynamic properties of the whole disc responding to the fatigue loading. The results revealed that the intervention of hyaluronic acid and genipin could recover the water content of the degenerated nucleus pulposus after rest, but block the water outflow during the fatigue loading. The genipin could slightly increase the elasticity of the degenerated nucleus pulposus and condense the delaminated anular fibrosus. Neither the intervention of hyaluronic acid nor the genipin recovered the viscoelasticity of the degenerated nucleus pulposus. The intervention of hyaluronic acid and genipin could recover the disc stiffness and energy dissipation capability of the degenerated disc. However, these effects are degraded by the fatigue loading. The results indicated that the crosslinker could better recover the structural and mechanical properties of the degenerated disc than the viscosupplement does. However, the susceptibility to the fatigue loading casts the doubt on the feasibility of crosslinker to treat the degenerated disc diseases. In conclusion, this dissertation proves that the disc mechanical functions are affected by the loading conditions and degeneration due to the change of disc hydration level and matrix pore size. The disc stiffness increased and the internal fluid flow capability decreased with degeneration. Neither the viscosupplement nor the crosslinker is feasible to reverse the full aspects of disc degenerative changes. New materials for treating degenerated disc should be studied in the future.