Advanced Regenerative Medicine ARM Phase II
Projects (completed)Regenerative Medicine for Compartment Syndrome
A Novel Protocol to Accelerate Nerve Regeneration Following Traumatic Combat Injury
Bioreactor-based Control of Inflammation in an In Vitro Model
“Regenerative Medicine for Compartment Syndrome”
Background: Compartment syndrome represents a major cause of morbidity in soldiers with traumatic extremity injuries. Compartment syndrome is also seen commonly in the civilian medical setting and therefore, the findings will have widespread clinical relevance. The swelling and associated increased intracompartmental pressure, seen in this syndrome, severely compromise blood flow resulting in ischemic necrosis of all tissues within the compartment (e.g., muscle, nerves, and associated structures). The loss of functional tissue is frequently severe enough to require amputation of the affected limb.
Typical outcomes of compartment syndrome with the current standard of care include the formation of scar tissue in place of the necrotic musculotendinous tissue of the involved compartment. The standard of care for peripheral compartment syndrome is fasciotomy with an attempt to salvage the viability of as much functional tissue as possible. Morbidity is high and includes severe aesthetic abnormalities (because of lost compartmental space).
The strategies described in this work take advantage of the advances in regenerative medicine that have identified bioinductive scaffolds that recruit autologous stem cells to promote functional tissue regeneration. Our work investigates a method for utilizing the inductive properties of extracellular matrix (ECM) as a scaffold for the recruitment of endogenous stem cells, and the attachment, proliferation, and spatial organization of these cells into functional tissue.
Our previous work has shown that xenogeneic extracellular matrix (ECM), usually of porcine origin and derived from either the small intestine or urinary bladder, have the ability to recruit autologous stem cells to the site of injury, facilitate their differentiation and spatial organization into site appropriate tissue, and restore tissue structure and function. Previous work has shown that manufactured forms of extracellular matrix (e.g., porcine small intestinal submucosa, porcine urinary bladder, porcine and bovine dermis, pericardium, among others) have the potential to promote constructive remodeling of damaged or missing body parts in place of inflammation and scarring.
The present work extends this concept by investigating methods for use of ECM scaffolds (with and without the presence of stem cells) in conjunction with traditional treatment methods to better facilitate regeneration of affected skeletal muscle compartments. In addition, we are developing methods of in-situ decellularization of the necrotic tissue while retaining the native extracellular matrix (autologous ECM). Stated differently, the extracellular matrix within the compartment would be isolated from its original cell population (which has now become necrotic) and this matrix would then be used as a template for tissue reconstruction.
In addition, these scaffold materials have been shown to promote an M2 (constructive remodeling) type of macrophage response as opposed to the more common M1 (cytotoxic, scar tissue forming) type of macrophage differentiation. The proposed strategies involve the combined use of xenogeneic ECM and the developed methodology for in situ decellularization of the necrotic tissue within the involved skeletal muscle compartment.
Thus, by decellularizing tissue in situ and leaving autologous extracellular matrix, and combining this matrix with xenogeneic matrix (if needed), the scaffold material may promote the reformation of functional tissue. It is also possible that future strategies will involve the addition of exogenously prepared autologous stem cells (e.g., bone marrow origin mesenchymal stem cells).
Bio: Dr. Stephen Badylak
Email: Dr. Stephen Badylak
Lee, W.P. Andrew
“A Novel Protocol to Accelerate Nerve Regeneration Following Traumatic Combat Injury”
Background: Per year, 50,000 people in the US undergo surgery for peripheral nerve injury. With reconstruction, nerve growth can be achieved; however, functional recovery is seldom reached. Composite tissue transplantation (CTA) has become a clinical reality and valuable treatment option after e.g. hand loss or a disfiguring injury of the face. Although acceptable functional return has been observed in some cases, motor and sensory return remains unsatisfactory in many others. In addition, trauma to the extremities and/or peripheral nerves is a major cause of disabling injuries in combat veterans. Novel treatments to augment nerve regeneration and accelerate functional recovery could be greatly useful in management and rehabilitation of combat neurotrauma as well as after hand transplantation subsequent to loss. Our goal therefore is to evaluate and optimize the functional outcomes in CTA. Erythropoietin (EPO) has been shown to profoundly improve nerve regeneration both centrally and peripherally, but its use is limited by its hematopoietic effects which may potentially lead to thrombotic events. We hypothesize that carbamylated erythropoietin (cEPO) – a form of EPO devoid of hematopoietic potential - will provide the same neuroprotective and neuroregenerative effects without stimulating erythropoiesis and thus enable accelerated functional recovery following peripheral nerve injury as well as CTA.
Bio: Dr. Andrew W.P. Lee
Johns Hopkins Outpatient Center
Main Office: Department of Plastic and Reconstructive Surgery
601 N. Caroline Street
Baltimore, MD 21287
“Bioreactor-based Control of Inflammation in an In Vitro Model”
Background: Dr. Vodovotz’s group has developed a series of mathematical models of inflammation and its interactions with tissue damage and healing in the related settings of trauma and sepsis, with the goal of understanding, predicting, and controlling inflammation. Our therapeutic goal is not to abolish inflammation per se but to reduce damage or dysfunction (i.e. promote healing) by modulating inflammation in a rational fashion. We have conceived of a self regulating device for individualized regulation of inflammation, which we have initiated in the present study. Future work would involve tailoring the device to modulate inflammation and promote healing and regeneration using our computational simulations as a guide.
Bio: Dr. Yoram Vodovotz
Email: Dr. Yoram Vodovotz