Research

Mechanical regulation of bone and vascular growth

Mechanical cues drive a wide array of biological processes. Advances in micro-electronic systems (MEMS) have allowed us to create small implantable sensors that permit real-time analysis of in vivo mechanical environments during musculoskeletal healing.

 

Schematic view of segmental defect fixation plate
Schematic view of a segmental defect fixation plate with an embedded strain sensor. Adapted from Klosterhoff, et al. J Biomech Eng 2017 Nov 139(11).

The implanted strain sensor combined with a transceiver wirelessly transmit quantitative measurements of the local mechanical environment during regeneration. When implanted in conjunction with therapies or tissue engineered constructs, strain sensors enable an advanced understanding of mechanobiology throughout the regenerative process, thus providing greater insight into the effectiveness of and mechanisms behind potential regenerative therapies.

Another goal is to understand temporal-mechanical interplay and its effects on regeneration. We use both pre-clinical and in vitro models to assess vascular and bone growth under different load conditions, considering both acute and delayed treatment models. This work is relevant to designing advanced patient-specific medical devices and rehabilitation protocols.

Growth factor mediated vascular and bone regeneration depend on mechanical stimuli and time of treatment. Top = vascular structure 12 weeks after bone injury under fixation with stiff and compliant plates (VOI = volume of interest) a) acute treatment b) delayed treatment. Bottom = bone and vascular network images 12 weeks after injury under stiff and compliant fixation with c) acute and d) delayed treatment. Adapted from Boerckel, et al. PNAS 2011 Sept; 108(37): E674-E680.

Growth factor mediated vascular and bone regeneration depend on mechanical stimuli and time of treatment. Top = vascular structure 12 weeks after bone injury under fixation with stiff and compliant plates (VOI = volume of interest) a) acute treatment b) delayed treatment. Bottom = bone and vascular network images 12 weeks after injury under stiff and compliant fixation with c) acute and d) delayed treatment. Adapted from Boerckel, et al. PNAS 2011 Sept; 108(37): E674-E680.

Treatment of traumatic musculoskeletal injury

Traumatic bone injury is nearly always accompanied by substantial damage to the surrounding muscle and soft tissue. These multi-tissue traumas are also known as composite injuries. Nonunion of large bone defects in composite injury is one of the largest subgroups of complications after severe trauma, comprising 50% of all patient outcomes. Significant muscle damage or loss compromises the bone healing process, likely due to impaired vascularization, increased potential for infection, and/or diminished availability of progenitor cells.

Whether recovery from a traumatic injury results in patient outcomes of functional healing or nonunion depends on many factors. These include (but are not limited to) defect size, the local immune environment, mechanics, and the availability/recruitment of bioactive factors and cells. We develop and test new treatments designed to intervene and stimulate complete healing where nonunion would otherwise result.

Our research seeks to identify factors that contribute to good clinical outcomes for composite injuries in order to design better therapeutic strategies. This may include exploring specific conditions of mechanical stimulation, immunomodulation, growth factor delivery, and advanced biomaterials design.

Sample materials studied for musculoskeletal regeneration
Sample materials studied for musculoskeletal regeneration. a) Heparin microparticles for controlled release of high dose bone-morphogenetic protein-2 (BMP-2), adapted from Hettiaratchi, et al. Biomaterials 2014 35: 7228-7238. b) porous space-filling titanium scaffold for bone and vascular regeneration, adapted from Duke Univ. (C. Kelly), unpublished. c) PCL (polycaprolactone) nanofiber mesh for cell adhesion, vascular intrusion, and hydrogel delivery support, adapted from Kolambkar, et al. Tissue Eng Part A. 2014 Jan; 20(1-2):398-409.

Disease-modifying osteoarthritis treatments

Osteoarthritis (OA) affects nearly 21 million people in the United States and is one of the leading causes of chronic disability. Changes in articular cartilage, subchondral bone, synovium, blood vessels, tendons, and muscle have all been implicated in osteoarthritis disease progression. Currently, only symptom management treatments are available to the patient population. One key research area for the Guldberg lab is to develop and evaluate disease modifying osteoarthritis drugs (DMOADs) and therapeutics in pre-clinical models.

To perform robust DMOAD evaluation, we have developed novel imaging techniques to analyze degenerative changes for multiple tissues in pre-clinical models of osteoarthritis. For example, articular cartilage degeneration, subchondral bone alterations, and osteophyte development can be measured with contrast based μcomputed tomography (μCT).

Contrast-enhanced μ-CT imaging
Contrast-enhanced μ-CT allows for visualization and quantification of joint tissue degeneration and therapeutic efficacy. a) Contrast enhancement methodology diagram showing that degenerated cartilage with lower proteoglycan content (right) results in diffusion of more anionic iodinated contrast agent molecules into the articular cartilage tissue, producing greater X-ray attenuation with μ-CT imaging. b) Cartilage morphology changes in the medial tibial plateau, depicted by μ-CT image analyses (left) and histology (right). Top = healthy; bottom = degenerated joints. Arrows indicate areas of articular cartilage degeneration in the form of surface roughness changes, lesions, and fibrillation. Scale bars = 1mm. Adapted from Reece, et al. Osteoarthritis and Cartilage 2018. 26(1):118-127.