Improved Delivery and Function of Myoblasts via Soluble TIPS Microcarriers

Incontinence is a debilitating condition with devastating social, economic and psychological consequences. A common cause is damage sustained during childbirth to the muscles that normally provide control of bowel movements. Current medical and surgical treatments are often inadequate. Emerging treatments involving the use of a patient's own muscle cells offer the possibility of restoring function to the damaged muscle, but improved methods for delivering the cells to ensure they survive and repair tissue are needed.

The aim of the proposed research is to demonstrate, through proof of principle, that muscle cells attached to the surface of a unique type of degradable polymer microsphere are more effective at restoring injured muscle compared with conventional methods of muscle cell delivery. The aim will be achieved through an interdisciplinary project involving biologists, clinicians and materials scientists. The experimental study will include investigating the optimal conditions for attachment of muscle cells to the microspheres; delivery of the cellularized microspheres to pre-clinical models of muscle injury; measurement of integration of the transplanted cells at the injury site; and ability of the transplanted cells to restore muscle contractility. In parallel to the experimental study we will establish women's views on the innovative therapy we are proposing, which will help us to design a therapeutic system best suited to the user's needs.

The outcome from the present study will provide timely, key information for the future development of the therapeutic system. The experimental outputs will be used to design future clinical trials investigating the safety and effectiveness of the treatment in faecally incontinent patients. Both the polymer microspheres and cell types being investigated are already being developed independently for other clinical uses, making transfer of findings from this project to the clinic for faecal incontinence much faster. If successful, the therapeutic system will have tremendous economic benefits to the UK NHS, as well as delivering social, economic and psychological benefits to patients.

The project aims to demonstrate proof of principle for an innovative therapeutic system for functional restoration of injured muscle using a combination of cell therapy and a novel degradable cell microcarrier device. The novelty of this approach is the use of TIPS microspheres for cell expansion and delivery, utilizing their advantageous features and avoiding the need for proteolytic cell detachment prior to delivery.

Optimal conditions for muscle progenitor cell attachment to TIPS microspheres with different porosities will be identified with primary cultures of myoblasts and mesoangioblasts derived from mouse and human tissues at different seeding densities using a range of dynamic and/or static regimens. External anal sphincter injury will be modelled in a pilot investigation by creating a transverse incision in the tibialis anterior of mice and evaluating the healing response. Delivery of the cellularized microspheres and repair of muscle injury will be investigated in three injury groups simulating repair at different stages after obstetric injury and compared with delivery of cell suspensions or microspheres alone. The muscle will be resected at 2 and 4 weeks after treatment and contractile properties measured using an organ bath and electrical field stimulation. Integration of transplanted cells with host muscle at the injury site and remodelling of tissue will be determined by histology combined with morphometric analysis of fibrosis and angiogenesis.

The findings from the experimental component of the project, combined with feedback from patient user groups, will contribute to the developmental pathway of the therapeutic system. The use of quality qualified TIPS microspheres combined with cell types currently being trialled in humans as advanced therapeutic medicinal products will accelerate future translation of the system into the clinic.

The project aims to enhance development and translation of a new treatment strategy to the clinic. The project will provide impact in several of the MRC strategic priority areas including delivery of new regenerative medicine products for treatment of disease (Research Priority Theme One; Strategic Aim Two), generation of positive economic impact (Strategic Aim One), and strengthening a skilled research workforce (Strategic Aim Four).

In the short-term (1-3 years), beneficiaries will include companies in the cell therapy industry, especially those that are beginning to explore the untapped market for faecal incontinence (FI). The cell types being investigated are already used as advanced therapeutic medicinal products in commercially-sponsored clinical trials for a variety of clinical conditions. However, existing pre-clinical and clinical data indicate improved methods are sought for delivery of cells. Successful outcomes from this project, combined with TIPS microspheres being quality qualified independently, will deliver a pre-clinically qualified device in readiness for partnership or out-licensing to cell therapy companies for clinical validation of an innovative product in humans and help foster UK economic competitiveness.

In the mid-term (3-5 years), the aim is to verify efficacy of the therapeutic system for delivering cells for the treatment of FI. Successful clinical validation of the therapeutic system will reduce the current economic and social burden of incontinence on the UK NHS and patient community. Although the primary beneficiaries from this project will be patients with FI caused by non-neurogenic damage to anal sphincter muscle, other beneficiaries of the technology will include patients with FI caused by primary degeneration of sphincter muscle. In addition to FI, the therapeutic system will also provide technology of potential value to other conditions associated with muscle insufficiency or where delivery of cells on TIPS microcarriers may prove advantageous e.g. Duchenne muscular dystrophy. Therefore, the intellectual property relating to further development of the device holds significant value for commercialisation. Dissemination of the project findings will help underpin a drive for innovative cell-based therapeutic interventions for this and other clinical conditions, thus boosting the UK economy.

In the longer-term (>5 years), after efficacy for repair of overt sphincter damage with the therapeutic system has been demonstrated, it is feasible to envisage it being applied to the prevention of incontinence in patients who have detectable sphincter disruption (based on future wider adoption of improved ultrasound imaging technology), but who do not currently experience symptoms. The patient perception of this type of approach will be ascertained from the patient participant focus group in the current project. Combined with clinical input for use, these data will influence design of the system and contribute to it meeting requirements of regulatory authorities.

The project will provide the PDRA with an excellent opportunity to develop career skills in a multidisciplinary environment at the laboratory-clinic interface, as well as gaining an insight into the translation pathway from bench-to-bedside. The project will equip the person with the breadth of skills needed to effectively understand the processes involved with developing new healthcare products and provide them with experience of how to establish links and subsequently work with industrial partners as the technology moves forward. These career development opportunities go beyond those typically offered in a pre-clinical research project and will provide the PDRA with key attributes highly sought after for academic-industrial partnerships, adding a skilled scientist to the burgeoning UK med-tech industry work force.