Mechanobiology is the new and emerging science based on the insight that mechanics is fundamental and essential alongside breakthrough biology for the discovery and translation of novel therapies and interventions for 21st Century medicine.
Oxford Mechanobiology is an interdisciplinary group of engineers, biologists and surgeons designing and building the in vitro discovery technologies that will underpin next generation therapies.
Traumatic high strain rate loading of the human body is common (5 road traffic deaths, 61 seriously injured every day, UK) and brings high personal and societal costs – £288M for Afghanistan UK veterans’ health care). Tissue healing is a complex and highly coordinated response to injury, in which multiple signals between cells at a local and at organ level are required to produce a functional and timely repair. In musculoskeletal tissues where mechanical function is key, mechanical signals play a critical role in providing an efficient, effective healing process. The synergy of mechanical and biological factors is becoming a central paradigm for understanding physiological processes including healing, with claims that faulty mechanosensation is the root cause of a host of serious diseases.
Mechanistic understanding is lacking at all stages of the physiological response to trauma:
The mechanical and physical response of the organised microstructural elements in tissue (protein fibrils, cell components)
The biological sequellae of the physical response
The link to local and systemic physiological derangement
The potential for pre-hospital interventions to mitigate
The potential to harness mechanical signals to accelerate and increase quality of tissue healing
Oxford Mechanobiology has developed a number of in vitro models for cell and tissue mechanobiology. Currently we are building functional organ-on-a-chip models suitable for modelling traumatic loading together with high strain rate loading facilities benefitting from high speed in situ imaging methods.
Rates of upper limb amputations following road traffic, industrial or agricultural accidents are high and rising in India with conservative figures from 2001 of 21M people living with disability. Victims are frequently wage-earning with dependents and a functional prosthetic hand could increase the likelihood of continuing employment, however current functional devices are not affordable.
A team at the Centre for Product Design and Manufacturing, Indian Institute of Science, Bangalore (IISc) made a breakthrough with new concepts for the design of affordable functional prostheses and in 2014 began a Wellcome Trust funded collaboration with Mark Thompson at the Institute of Biomedical Engineering at Oxford with the aim of developing and commercialising these designs. The IISc contributed expertise in affordable and appropriate design, while the Oxford team supported biomechanical assessment, clinical trial design and commercialisation.
The IISc team have recently launched a spin-out, Grasp Bionics, to commercialise the PURAK affordable arm design together with project partners Mobility India.
Soft tissue in situ imaging and XRD
Mechanical testing with in situ imaging offers new insight into normal physiological function and response to damaging loading.
Multiphoton microscopy (MPM) images collagen, elastin and other proteins with no exogenous staining permits image-based cell-level strain estimation. Ultra-small and wide-angle X-ray scattering (USAXS and WAXS) using the quasi-crystalline structure of proteins estimate in situ strain at molecular and fibrillar level. Collagen and elastin fibrils constraining swelling glycosaminoglycans is a constant structural motif for soft tissue so techniques and models developed for one tissue may be readily employed for multiple others.
Tendons resist millions of cycles at high load, however mechanobiological mechanisms of homeostasis and adaptation are poorly understood. MPM of fresh tendon samples showed the pericellular environment dominated by elastin motivating a finite element model that followed cell strain measurement well (Fig 1).Enzymatic removal of elastin confirmed the likely pericellular rather than macroscopic role of this protein. Mechanical overload that did not affect macroscopic stiffness still altered tendon stiffness at fibrillar (USAXS) and molecular (WAXS) levels, possibly localising damage to molecular cross links.
In peripheral nerves the microscopic mechanisms of damage from repetitive mechanical loading and trauma that can provoke functional deficit and pain are little understood. USAXS, WAXS and video extensometry showed similar collagen fibril recruitment and deformation mechanisms to tendons and highlighted the high relative stiffness of myelin sheaths protecting the axons from radial compression. In situ tensile loading with sodium ion channel staining and digital image correlation showed axons were also protected by uncrimping mechanisms in collagen fibrils and the axons themselves.
Bladder sustains large cyclic deformations and in situ uniaxial loading and MPM revealed widely differing mechanisms in the two tissue layers: low strain unfolding of the ruffled lamina propria then followed by rapid stiffening as two families of collagen fibrils in the detrusor engage at higher strains.
In both stiff and highly compliant tissues a mathematical analysis of collagen fibril recruitment probability density function (PDF) was supported by imaging enabling this PDF to be estimated from macroscopic stress-stretch characteristics.